C17, c20, and c21 substituted neuroactive steroids and their methods of use

ABSTRACT

Described herein are neuroactive steroids or a pharmaceutically acceptable salt thereof. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. Also provided are pharmaceutical compositions comprising a compound described herein and methods of use and treatment, e.g., such as for inducing sedation and/or anesthesia.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Ser. No. 62/360,813 filed Jul.11, 2016, U.S. Ser. No. 62/360,847 filed Jul. 11, 2016, and U.S. Ser.No. 62/424,803 filed Nov. 18, 2016, which are incorporated herein byreference.

BACKGROUND

Brain excitability is defined as the level of arousal of an animal, acontinuum that ranges from coma to convulsions, and is regulated byvarious neurotransmitters. In general, neurotransmitters are responsiblefor regulating the conductance of ions across neuronal membranes. Atrest, the neuronal membrane possesses a potential (or membrane voltage)of approximately −70 mV, the cell interior being negative with respectto the cell exterior. The potential (voltage) is the result of ion (K⁺,Na⁻, Cl⁻, organic anions) balance across the neuronal semipermeablemembrane. Neurotransmitters are stored in presynaptic vesicles and arereleased under the influence of neuronal action potentials. Whenreleased into the synaptic cleft, an excitatory chemical transmittersuch as acetylcholine will cause membrane depolarization, e.g., a changeof potential from −70 mV to −50 mV. This effect is mediated bypostsynaptic nicotinic receptors which are stimulated by acetylcholineto increase membrane permeability to Na⁺ ions. The reduced membranepotential stimulates neuronal excitability in the form of a postsynapticaction potential.

In the case of the GABA receptor complex (GRC), the effect on brainexcitability is mediated by GABA, a neurotransmitter. GABA has aprofound influence on overall brain excitability because up to 40% ofthe neurons in the brain utilize GABA as a neurotransmitter. GABAregulates the excitability of individual neurons by regulating theconductance of chloride ions across the neuronal membrane. GABAinteracts with its recognition site on the GRC to facilitate the flow ofchloride ions down an electrochemical gradient of the GRC into the cell.An intracellular increase in the levels of this anion causeshyperpolarization of the transmembrane potential, rendering the neuronless susceptible to excitatory inputs, i.e., reduced neuronexcitability. In other words, the higher the chloride ion concentrationin the neuron, the lower the brain excitability and level of arousal.

It is well-documented that the GRC is responsible for the mediation ofanxiety, seizure activity, and sedation. Thus, GABA and drugs that actlike GABA or facilitate the effects of GABA (e.g., the therapeuticallyuseful barbiturates and benzodiazepines (BZs), such as Valium®) producetheir therapeutically useful effects by interacting with specificregulatory sites on the GRC. Accumulated evidence has now indicated thatin addition to the benzodiazepine and barbiturate binding site, the GRCcontains at least one distinct site for interaction with neuroactivesteroids. See, e.g., Lan, N. C. et al., Neurochem. Res. (1991)16:347-356.

Neuroactive steroids can occur endogenously. The most potent endogenousneuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and3α-21-dihydroxy-5-reduced pregnan-20-one, metabolites of hormonalsteroids progesterone and deoxycorticosterone, respectively. The abilityof these steroid metabolites to alter brain excitability was recognizedin 1986 (Majewska, M. D. et al., Science 232:1004-1007 (1986); Harrison,N. L. et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)).

New and improved neuroactive steroids are needed that act as modulatingagents for brain excitability, as well as agents for the prevention andtreatment of CNS-related diseases. The compounds, compositions, andmethods described herein are directed toward this end.

SUMMARY OF THE INVENTION

Compounds as described herein, act, in certain embodiments, as GABAmodulators, e.g., effecting the GABA_(A) receptor in either a positiveor negative manner. As modulators of the excitability of the centralnervous system (CNS), as mediated by their ability to modulate GABA_(A)receptor, such compounds are expected to have CNS-activity.

In an aspect, provided herein is a compound of the Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: each of R², R⁴,R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen, halogen, cyano,nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, NHC(═O)R^(A1),—S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), wherein each instance ofR^(A1) is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attachedto an oxygen atom, a sulfur protecting group when attached to a sulfuratom, a nitrogen protecting group when attached to a nitrogen atom, ortwo R^(A1) groups are joined to form an heterocyclic or heteroaryl ring;and R^(A2) is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,or heteroaryl; or R^(11a) and R^(11b) together with the carbon atom towhich they are attached form a carbocyclyl, heterocyclyl, or —C(═O)—; R³is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; eachof R^(17a) and R^(17b) is independently hydrogen, halogen, cyano, nitro,alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,—OR^(A1), —SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1), —S(═O)R, —SO₂R^(A2), or—S(═O)₂OR^(A1), wherein at least one of R^(11a) and R^(11b) is nothydrogen; R¹⁹ is hydrogen or alkyl (e.g., unsubstituted alkyl orsubstituted alkyl (e.g., —C(R^(C))₂OR^(A1), wherein R^(C) is hydrogen oralkyl)); R⁵ is absent or hydrogen; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent.

In some embodiments, R¹⁹ is hydrogen or alkyl. In some embodiments, R¹⁹is unsubstituted alkyl. In some embodiments, R¹⁹ is substituted alkyl.In some embodiments, R¹⁹ is —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, or—CH₂OCH(CH₃)₂.

In some embodiments, R² is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R² is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R² is hydrogen.

In some embodiments, R³ is alkyl, alkenyl, carbocyclyl, heterocyclyl,aryl, or heteroaryl. In some embodiments, R³ is alkyl (e.g., substitutedor unsubstituted alkyl). In some embodiments, R³ is methyl and ethyl(e.g., substituted or unsubstituted alkyl).

In some embodiments, R⁴ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁴ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁴ is hydrogen.

In some embodiments,

represents a single bond and R⁵ is hydrogen. In some embodiments, R⁵ isabsent, and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond.

In some embodiments, R⁶ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁶ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁶ is hydrogen.

In some embodiments, R⁷ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁷ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁷ is hydrogen.

In some embodiments, R^(11a) is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂ orR^(11a) and R together with the carbon atom to which they are attachedform —C(═O)—. In some embodiments, R^(11a) is hydrogen, halogen, alkyl,or —OR^(A1). In some embodiments, R^(11a) and R^(11b) together with thecarbon atom to which they are attached form —C(═O)—. In someembodiments, R^(11a) and R^(11b) are hydrogen.

In some embodiments, each of R², R⁴, R⁶, R⁷, R^(11a), and R^(11b) isindependently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. In some embodiments,each of R², R⁴, R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen,halogen, alkyl, or —OR^(A1). In some embodiments, R², R⁴, R⁶, R⁷,R^(11a), and R^(11b) are hydrogen.

In some embodiments, each of R^(17a) and R^(17b) is independentlyhydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, —SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1)—S(═O)R^(A2),—SO₂R^(A2) or —S(═O)₂OR^(A1), wherein at least one of R^(17a) andR^(17b) is not hydrogen. In some embodiments, each of R^(17a) andR^(17b) is independently hydrogen, halogen, nitro, alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, —SR^(A1), —N(R^(A1))₂,—NHC(═O)R^(A1)—S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), wherein atleast one of R^(17a) and R^(17b) is not hydrogen.

In some embodiments, R^(17a) is halogen, cyano, nitro, alkyl,carbocyclyl, heterocyclyl, —OR^(A1)—, —SR^(A1), —N(R^(A1))₂,—NHC(═O)R^(A1), —S(═O)R^(A2), or —SO₂R^(A2). In some embodiments,R^(17a) is halogen, nitro, alkyl, carbocyclyl, heterocyclyl, —OR^(A1),—SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1), —S(═O)R^(A2), or —SO₂R^(A2). Insome embodiments, R^(17a) is halogen, cyano, nitro, alkyl, —OR^(A1),—SR^(A1), or —N(R^(A1))₂.

In an aspect, provided herein is a compound of the Formula II:

or a pharmaceutically acceptable salt thereof, wherein: each of R², R⁴,R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen, halogen, cyano,nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), whereineach instance of R^(A1) is independently hydrogen, alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygenprotecting group when attached to an oxygen atom, a sulfur protectinggroup when attached to a sulfur atom, a nitrogen protecting group whenattached to a nitrogen atom, or two R^(A1) groups are joined to form anheterocyclic or heteroaryl ring; and R^(A2) is alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R^(11a) and R^(11b)together with the carbon atom to which they are attached form acarbocyclyl, heterocyclyl, or —C(═O)— group; R³ is hydrogen, alkyl,alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; A is alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, —OR^(A1), —SR^(A1), or—N(R^(A1))₂; R¹⁹ is hydrogen or alkyl (e.g., unsubstituted alkyl (e.g.,—CH₃) or substituted alkyl (e.g., —C(R^(C))₂OR^(A1), wherein R^(C) ishydrogen or alkyl)); R⁵ is absent or hydrogen; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent.

In some embodiments, A is hydrogen, alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, or —OR^(A1).

In some embodiments, R¹⁹ is hydrogen. In some embodiments, R¹⁹ is alkyl(e.g., substituted or unsubstituted alkyl). In some embodiments, R¹⁹ is—CH₃ or —CH₂CH₃. In some embodiments, R¹⁹ is —C(R^(C))₂OR^(A1). In someembodiments, R¹⁹ is —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, or —CH₂OCH(CH₃)₂.

In some embodiments, R² is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R² is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R² is hydrogen.

In some embodiments, R³ is alkyl (e.g., substituted or unsubstitutedalkyl). In some embodiments, R³ is methyl and ethyl (e.g., substitutedor unsubstituted methyl, substituted or unsubstituted ethyl).

In some embodiments, R⁴ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁴ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁴ is hydrogen.

In some embodiments,

represents a single bond and R⁵ is hydrogen. In some embodiments, R⁵ isabsent, and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond.

In some embodiments, R⁶ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁶ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁶ is hydrogen.

In some embodiments, R⁷ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁷ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁷ is hydrogen.

In some embodiments, R^(11a) is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, orR^(11a) and R^(11b) together with the carbon atom to which they areattached form —C(═O)—. In some embodiments, R^(11a) is hydrogen,halogen, alkyl, or —OR^(A1). In some embodiments, R^(11a) and R^(11b)together with the carbon atom to which they are attached form —C(═O)—.In some embodiments, R^(11a) and R^(11b) are hydrogen.

In some embodiments, each of R², R⁴, R⁶, R⁷, R^(11a), and R^(11b) isindependently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. In some embodiments,each of R², R⁴, R⁶, R⁷, R^(11a), and R^(11b) is hydrogen, halogen,alkyl, or —OR^(A1). In some embodiments, each of R², R⁴, R⁶, R⁷,R^(11a), and R^(11b) is hydrogen.

In some embodiments, the compound of Formula (II) is a compound of theFormula (II-a) or (II-b):

In some embodiments, the compound of Formula (II) is a compound of theFormula (II-c):

each of R^(21a) and R^(21b) is independently hydrogen, halogen, cyano,nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR^(A1)—, S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1); or R^(21a)and R^(21b) together with the carbon atom to which they are attachedform a carbocyclyl, heterocyclyl, or —C(═O)— group; Q is hydrogen,halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂; andn is an integer selected from 1, 2, and 3.

In some embodiments, the compound of Formula (II) is a compound of theFormula (II-dl):

In an aspect, provided herein is a compound of the Formula (III):

or a pharmaceutically acceptable salt thereof, wherein: each of R², R⁴,R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen, halogen, cyano,nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), whereineach instance of R^(A1) is independently hydrogen, alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygenprotecting group when attached to an oxygen atom, a sulfur protectinggroup when attached to a sulfur atom, a nitrogen protecting group whenattached to a nitrogen atom, or two R^(A1) groups are joined to form anheterocyclic or heteroaryl ring; and R^(A2) is alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R^(11a) and R^(11b)together with the carbon atom to which they are attached form acarbocyclyl, heterocyclyl, or —C(═O)— group; Q is hydrogen, halogen,cyano, nitro, alkyl, alkenyl, alkynyl, —OR^(A1), —SR^(A1), or—N(R^(A1))₂; R¹⁹ is unsubstituted alkyl; R⁵ is absent or hydrogen; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent.

In an aspect, provided herein is a compound of the Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein: each of R², R⁴,R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen, halogen, cyano,nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), whereineach instance of R^(A1) is independently hydrogen, alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygenprotecting group when attached to an oxygen atom, a sulfur protectinggroup when attached to a sulfur atom, a nitrogen protecting group whenattached to a nitrogen atom, or two R^(A1) groups are joined to form anheterocyclic or heteroaryl ring; and R^(A2) is alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R^(11a) and R^(11b)together with the carbon atom to which they are attached form acarbocyclyl, heterocyclyl, or —C(═O)— group; R³ is alkyl, alkenyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl; Q is halogen, cyano,nitro, heterocyclyl linked through a C atom, aryl, heteroaryl linkedthrough a C atom, —O-alkenyl, —O-alkynyl, —SR^(A1), —N(R^(A1))₂,—NHC(═O)R^(A1), —NHC(═O)OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or—S(3)²OR^(A1); R¹⁹ is —C(R^(C))₂OR^(A1) wherein R^(C) is hydrogen oralkyl; R⁵ is absent or hydrogen; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent.

In an aspect, provided herein is a compound of the Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: each of R², R⁴,R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen, halogen, cyano,nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1),—S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), wherein each instance ofR^(A1) is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attachedto an oxygen atom, a sulfur protecting group when attached to a sulfuratom, a nitrogen protecting group when attached to a nitrogen atom, ortwo R^(A1) groups are joined to form an heterocyclic or heteroaryl ring;and R² is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl; or R^(11a) and R^(11b) together with the carbon atom towhich they are attached form a carbocyclyl, heterocyclyl, or —C(═O)—; R³is hydrogen, alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl; each of R^(11a) and R^(11b) is independently hydrogen,halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂,—NHC(═O)R^(A1), —S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), wherein atleast one of R^(17a) and R^(17b) is not hydrogen; R¹⁹ is hydrogen oralkyl (e.g., unsubstituted alkyl or substituted alkyl (e.g.,—C(R^(C))₂OR^(A1) wherein R^(C) is hydrogen or alkyl)); R⁵ is absent orhydrogen; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent.

In some embodiments, R¹⁹ is hydrogen or alkyl. In some embodiments, R¹⁹is unsubstituted alkyl. In some embodiments, R¹⁹ is substituted alkyl.In some embodiments, R¹⁹ is —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, or—CH₂OCH(CH₃)₂.

In some embodiments, R² is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R² is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R² is hydrogen.

In some embodiments, R³ is alkyl, alkenyl, carbocyclyl, heterocyclyl,aryl, or heteroaryl. In some embodiments, R³ is alkyl (e.g., substitutedor unsubstituted alkyl), alkenyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl. In some embodiments, R³ is methyl and ethyl (e.g.,substituted or unsubstituted alkyl).

In some embodiments, R⁴ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁴ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁴ is hydrogen.

In some embodiments,

represents a single bond and R⁵ is hydrogen. In some embodiments, R⁵ isabsent, and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond.

In some embodiments, R⁶ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁶ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁶ is hydrogen.

In some embodiments, R⁷ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁷ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁷ is hydrogen.

In some embodiments, R^(11a) is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, orR^(11a) and R^(11b) together with the carbon atom to which they areattached form —C(═O)—. In some embodiments, R^(11a) is hydrogen,halogen, alkyl, or —OR^(A1). In some embodiments, R^(11a) and R^(11b)together with the carbon atom to which they are attached form —C(═O)—.In some embodiments, R^(11a) and R^(11b) are hydrogen.

In some embodiments, each of R², R⁴, R⁶, R⁷, R^(11a), and R^(11b) isindependently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. In some embodiments,each of R², R⁴, R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen,halogen, alkyl, or —OR^(A1). In some embodiments, R², R⁴, R⁶, R⁷,R^(11a), and R^(11b), are hydrogen.

In some embodiments, each of R^(17a) and R^(17b) is independentlyhydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, —SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1)—S(═O)R^(A2),—SO₂R^(A2) or —S(═O)₂OR^(A1), wherein at least one of R^(17a) andR^(17b) is not hydrogen. In some embodiments, each of R^(17a) andR^(17b) is independently hydrogen, halogen, nitro, alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, —SR^(A1), —N(R^(A1))₂,—NHC(═O)R^(A1)—S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), wherein atleast one of R^(17a) and R^(17b) is not hydrogen.

In some embodiments, R^(17a) is halogen, cyano, nitro, alkyl,carbocyclyl, heterocyclyl, —OR^(A1), —SR^(A1), —N(R^(A1))₂,—NHC(═O)R^(A1), —S(═O)R^(A2), or —SO₂R^(A1). In some embodiments,R^(11a) is halogen, nitro, alkyl, carbocyclyl, heterocyclyl, —OR^(A1),—SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1), —S(═O)R^(A2), or —SO₂R^(A2). Insome embodiments, R^(11a) is halogen, cyano, nitro, alkyl, —OR^(A1),—SR^(A1), or —N(R^(A1))₂.

In some embodiments, the compound is:

or a pharmaceutically acceptable salt thereof.

In an aspect, provided herein is a compound of the Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: each of R², R⁴,R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen, halogen, cyano,nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), whereineach instance of R^(A1) is independently hydrogen, alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygenprotecting group when attached to an oxygen atom, a sulfur protectinggroup when attached to a sulfur atom, a nitrogen protecting group whenattached to a nitrogen atom, or two R^(A1) groups are joined to form anheterocyclic or heteroaryl ring; and R^(A2) is alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R^(11a) and R^(11b)together with the carbon atom to which they are attached form acarbocyclyl, heterocyclyl, or —C(═O)— group; R³ is hydrogen, alkyl,alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; A is alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, —OR^(A1), —SR^(A1), or—N(R^(A1))₂; R¹⁹ is hydrogen or alkyl (e.g., unsubstituted alkyl (e.g.,—CH₃) or substituted alkyl (e.g., —C(R^(C))₂OR^(A1), wherein R^(C) ishydrogen or alkyl)); R⁵ is absent or hydrogen; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent.

In some embodiments, A is hydrogen, alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, or —OR^(A1).

In some embodiments, R¹⁹ is hydrogen. In some embodiments, R¹⁹ is alkyl(e.g., substituted or unsubstituted alkyl). In some embodiments, R¹⁹ is—CH₃ or —CH₂CH₃. In some embodiments, R¹⁹ is —C(R^(C))₂OR^(A1). In someembodiments, R¹⁹ is —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, or —CH₂OCH(CH₃)₂.

In some embodiments, R² is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R² is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R² is hydrogen.

In some embodiments, R³ is alkyl (e.g., substituted or unsubstitutedalkyl). In some embodiments, R³ is methyl and ethyl (e.g., substitutedor unsubstituted methyl, substituted or unsubstituted ethyl).

In some embodiments, R⁴ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁴ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁴ is hydrogen.

In some embodiments,

represents a single bond and R⁵ is hydrogen. In some embodiments, R⁵ isabsent, and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond.

In some embodiments, R⁶ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁶ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁶ is hydrogen.

In some embodiments, R⁷ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁷ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁷ is hydrogen.

In some embodiments, R^(11a) is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, orR^(11a) and R^(11b) together with the carbon atom to which they areattached form —C(═O)—. In some embodiments, R^(11a) is hydrogen,halogen, alkyl, or —OR^(A1). In some embodiments, R^(11a) and R^(11b)together with the carbon atom to which they are attached form —C(═O)—.In some embodiments, R^(11a) and R^(11b) are hydrogen.

In some embodiments, each of R², R⁴, R⁶, R⁷, R^(11a), and R^(11b) isindependently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. In some embodiments,each of R², R⁴, R⁶, R⁷, R^(11a), and R^(11b) is hydrogen, halogen,alkyl, or —OR^(A1). In some embodiments, each of R², R⁴, R⁶, R⁷,R^(11a), and R^(11b) is hydrogen.

In some embodiments, the compound of Formula (II) is a compound of theFormula (II-a) or (II-b):

In some embodiments, the compound of Formula (I) is a compound of theFormula (II-c):

each of R^(21a) and R^(21b) is independently hydrogen, halogen, cyano,nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1); or R^(11a)and R^(21b) together with the carbon atom to which they are attachedform a carbocyclyl, heterocyclyl, or —C(═O)— group; Q is hydrogen,halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂; andn is an integer selected from 1, 2, and 3.In some embodiments, the compound of Formula (II) is a compound of theFormula (II-d):

In an aspect, provided herein is a compound of the Formula (III-a):

or a pharmaceutically acceptable salt thereof, wherein: each of R², R⁴,R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen, halogen, cyano,nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), whereineach instance of R^(A1) is independently hydrogen, alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygenprotecting group when attached to an oxygen atom, a sulfur protectinggroup when attached to a sulfur atom, a nitrogen protecting group whenattached to a nitrogen atom, or two R^(A1) groups are joined to form anheterocyclic or heteroaryl ring; and R^(A2) is alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R^(11a) and R^(11b)together with the carbon atom to which they are attached form acarbocyclyl, heterocyclyl, or —C(═O)— group; Q is hydrogen, halogen,cyano, nitro, alkyl, alkenyl, alkynyl, —OR^(A1), —SR^(A1), or—N(R^(A1))₂; R¹⁹ is unsubstituted alkyl; R⁵ is absent or hydrogen; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent.

In an aspect, provided herein is a compound of the Formula (III-b):

or a pharmaceutically acceptable salt thereof, wherein: each of R², R⁴,R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen, halogen, cyano,nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), whereineach instance of R^(A1) is independently hydrogen, alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygenprotecting group when attached to an oxygen atom, a sulfur protectinggroup when attached to a sulfur atom, a nitrogen protecting group whenattached to a nitrogen atom, or two R^(A1) groups are joined to form anheterocyclic or heteroaryl ring; and R^(A2) is alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R^(11a) and R^(11b)together with the carbon atom to which they are attached form acarbocyclyl, heterocyclyl, or —C(═O)— group; R³ is alkyl, alkenyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl; Q is halogen, cyano,nitro, heterocyclyl linked through a C atom, aryl, heteroaryl linkedthrough a C atom, —O-alkenyl, —O-alkynyl, —SR^(A1), —N(R^(A1))₂,—NHC(═O)R^(A1), —NHC(═O)OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or—S(═O)₂OR^(A1); R¹⁹ is —C(R^(C))₂OR^(A1), wherein R^(C) is hydrogen oralkyl; R⁵ is absent or hydrogen; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent.

In an aspect, provided herein is a compound of Formula (1-A):

or a pharmaceutically acceptable salt thereof, wherein: R³ is alkyl,alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each of R^(X)and R^(Y) is independently hydrogen, aryl, or alkyl, or R^(X) and R^(Y)are joined together to form a 3-10 membered heterocyclic ring; R¹⁹ ishydrogen or alkyl (e.g., unsubstituted alkyl or substituted alkyl (e.g.,—C(R^(C))₂OR^(A1), wherein R^(C) is hydrogen or alkyl)); R⁵ is absent orhydrogen;

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent; and a is 0 or 1; provided that R^(X)and R^(Y) are joined together to form a 3-8 membered heterocyclic ringonly when a is 0.

In some embodiments, R^(X) and R^(Y) are not both hydrogen. In someembodiments, R³ is alkyl. In some embodiments, R¹⁹ is hydrogen.

In some embodiments, the compound is a compound of Formula (1-A-1)

wherein each instance of R^(Y4) is independently alkyl, cyano, or halo;and e is 0, 1, 2, 3, 4, or 5.

In some embodiments, each instance of R^(Y4) is independently hydrogen,—CH₃, —CN, or —F. In some embodiments, e is 3. In some embodiments,R^(X) is hydrogen. In some embodiments, each instance of R^(Y4) isindependently hydrogen, —CH₃, —CN, or —F, R^(X) is hydrogen, and e is 3.In some embodiments, each instance of R^(Y4) is independently hydrogen,—CH₃, —CN, or —F, R^(X) is hydrogen, and e is 2. In some embodiments, eis 1. In some embodiments, R^(Y4) is —F. In some embodiments, R^(Y4)is-F and e is 1.

In some embodiments, the compound is a compound of Formula (1-A-2)

In some embodiments, each instance of R^(Y4) is independently hydrogen,—CH₃, —CN, or —F. In some embodiments, e is 3. In some embodiments,R^(X) is hydrogen. In some embodiments, each instance of R^(Y4) isindependently hydrogen, —CH₃, —CN, or —F, R^(X) is hydrogen, and e is 3.In some embodiments, each instance of R^(Y4) is independently hydrogen,—CH₃, —CN, or —F, R^(X) is hydrogen, and e is 2. In some embodiments, eis 1. In some embodiments, R^(Y4) is —F.

In some embodiments, the compound is a compound of Formula (1-A-3)

wherein each of R^(Y1) and R^(Y2) is independently alkyl, cycloalkyl,heterocycyl, aryl, or heteroaryl; and b=0, 1, 2, 3.

In some embodiments, R^(Y1) and R^(Y2) are not both —CH(CH₃)₂.

In some embodiments, the compound is a compound of Formula (1-A-4)

In some embodiments, R^(Y1) is hydrogen, —CH₃, or —CH₂CH₃, —CH(CH₃)₂, orcycloalkyl. In some embodiments, R³ is —CH₃, —CF₃, —CH₂OCH₃,—CH₂OCH₂CH₃. In some embodiments, R^(Y2) is heterocyclyl, aryl, orheteroaryl. In some embodiments, R^(Y2) is aryl substituted with 0-5occurrences of —CH₃, —CN, —F, —CF₃, or combinations thereof orheteroaryl substituted with 0-5 occurrences of —CH₃, —CN, —F, —CF₃.

In some embodiments, R^(Y2) is aryl substituted with 0-5 occurrences of—CH₃, —CN, —F, —CF₃, or R^(X) is hydrogen, —CH₃, or —CH₂CH₃. In someembodiments, R^(Y2) is aryl substituted with 0-5 occurrences of —CH₃,—CN, —F, —CF₃.

In some embodiments, the compound is a compound of Formula (1-A-5)

wherein each occurrence of R^(Y3) is aryl or heteroaryl, or two R^(Y3)groups are joined together to form a 6-membered ring; c is 0, 1, 2, or3; and d is 0, 1, 2, or 3.

In some embodiments, the compound is a compound of Formula (1-A-6)

In some embodiments, if d is 2, then two R^(Y3) groups are joinedtogether to form aryl. In some embodiments, R^(Y2) is aryl substitutedwith 0-5 occurrences of —CH₃, —CN, —F, —CF₃. In some embodiments, thecompound is a compound of Formula (1-A-7) or Formula (1-A-8)

In some embodiments, R^(Y2) is aryl substituted with 0-5 occurrences of—CH₃, —CN, —F, —CF₃, or R³ is —CH₃, —CF₃, —CH₂OCH₃, —CH₂OCH₂CH₃.

In an aspect, provided herein is a compound of Formula (2-A),

or a pharmaceutically acceptable salt thereof, wherein R³ is —CH₃, —CF₃,—CH₂OCH₃, —CH₂OCH₂CH₃; R¹⁹ is hydrogen, —CH₃, or —CH₂OR^(A1), whereinR^(A1) is optionally substituted alkyl; R³ is —CH₃, —CF₃, —CH₂OCH₃,—CH₂OCH₂CH₃; R^(17a) is —NR^(A2)R^(A3), —N(R1)C(O)R^(A2),—N(R1)SO₂R^(A2), —OR^(A3), cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each of R^(A2) and R^(A3) is independently hydrogen,carbocyclyl, heterocyclyl, aryl, heteroaryl, or —OR^(A4), wherein R^(A4)is hydrogen or alkyl; or R^(17A) is

wherein A is oxazolyl or thiazolyl; R^(17B) is hydrogen, hydroxyl,alkyl, or alkoxy; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent; provided that: when R^(17a) isoxazolyl or

then R^(17b) is not hydrogen, or when R^(17a) is heterocyclyl, then R¹⁹is hydrogen, or when R^(17a) is —OR^(A4), then R¹⁹ is hydrogen.

In some embodiments, R^(17a) is —NR^(A2)R^(A3), —N(R1)C(O)R^(A2),—N(R1)SO₂R^(A2). In some embodiments, R^(17a) is aryl, heteroaryl,cycloalkyl, or heterocyclyl. In some embodiments, R¹⁹ is hydrogen. Insome embodiments, R^(17a) is heteroaryl. In some embodiments, R^(17a) isheteroaryl and R¹⁹ is hydrogen. In some embodiments, R^(17a) is pyridyland R¹⁹ is hydrogen.

In an aspect, provided herein is a compound of Formula (3-A)

or a pharmaceutically acceptable salt thereof, wherein R¹⁹ is hydrogenor alkyl; Ria is nitro or alkoxy (e.g., —OCH₃); each of R², R⁴, R^(11a),or R^(11b) is independently hydrogen, alkyl, or alkoxy, or R^(11a) andR^(11b) are joined together to form oxo;

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent; and R⁵ is absent or hydrogen asdetermined by valency; provided that, when R², R^(11a), and R^(11b) arehydrogen, then R⁴ is alkyl, or when R⁴, R^(11a), and R^(11b) arehydrogen, then R² is alkyl, or when R⁴ is hydrogen, then R² is —OH oralkoxy, R^(11a) is hydrogen, and R^(11b) is —OH or alkoxy, or R² is —OHor alkoxy and R^(11a) and R^(11b) are joined together to form oxo.

In some embodiments, R⁴ is hydrogen, R² is —OH or alkoxy, R^(11a) ishydrogen, and R^(11b) is —OH or alkoxy. In some embodiments, R⁴ ishydrogen, R² is —OH or alkoxy, and R^(11a) and R^(11b) are joinedtogether to form oxo. In some embodiments, R^(17a) is nitro. In someembodiments, R^(17a) is alkoxy. In some embodiments, R^(17a) is methoxyand R² is methyl.

In an aspect, also provided herein are compounds described in Table 1 orpharmaceutically acceptable salts thereof.

In an aspect, provided herein is a pharmaceutical composition comprisinga compound described herein (e.g., a compound of the Formula (I),Formula (II), Formula (III), or Formula (IV), Formula (1-A), Formula(2-A), or Formula (3-A)) and a pharmaceutically acceptable excipient.

In an aspect, provided herein is a method of inducing sedation and/oranesthesia in a subject, comprising administering to the subject aneffective amount of a compound described herein (e.g., a compound of theFormula (I), Formula (II), Formula (III), or Formula (IV), Formula(1-A), Formula (2-A), or Formula (3-A)), or a pharmaceuticallyacceptable salt thereof.

In an aspect, provided herein is a method of administering an effectiveamount of a compound, a pharmaceutically acceptable salt thereof, orpharmaceutical composition of a compound described herein (e.g., acompound of the Formula (I), Formula (II), Formula (III), or Formula(IV), Formula (1-A), Formula (2-A), or Formula (3-A)), to a subject inneed thereof, wherein the subject experiences sedation and/or anesthesiawithin two hours of administration. In some embodiments, the subjectexperiences sedation and/or anesthesia within one hour ofadministration. In some embodiments, the subject experiences sedationand/or anesthesia instantaneously. In some embodiments, the compound isadministered by intravenous administration. In some embodiments, thecompound is administered chronically.

In some embodiments, the subject is a mammal. In some embodiments, thesubject is a human.

In some embodiments, the compound is administered in combination withanother therapeutic agent.

In an aspect, provided herein is a method for treating seizure in asubject, comprising administering to the subject an effective amount ofa compound described herein (e.g., a compound of the Formula (I),Formula (II), Formula (III), or Formula (IV), Formula (1-A), Formula(2-A), or Formula (3-A)).

In an aspect, provided herein is a method for treating epilepsy orstatus epilepticus in a subject, the method comprising administering tothe subject an effective amount of a compound described herein (e.g., acompound of the Formula (I), Formula (II), Formula (III), or Formula(IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

In an aspect, provided herein is a method for treating a neuroendocrinedisorder or dysfunction in a subject, comprising administering to thesubject an effective amount of a compound described herein (e.g., acompound of the Formula (I), Formula (II), Formula (III), or Formula(IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

In an aspect, provided herein is a method for treating aneurodegenerative disease or disorder in a subject, comprisingadministering to the subject an effective amount of a compound describedherein (e.g., a compound of the Formula (I), Formula (II), Formula(III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

In an aspect, provided herein is a method for treating a movementdisorder or tremor in a subject, comprising administering to the subjectan effective amount of a compound described herein (e.g., a compound ofthe Formula (I), Formula (II), Formula (III), or Formula (IV), Formula(1-A), Formula (2-A), or Formula (3-A)).

In an aspect, provided herein is a method for treating a mood disorderor anxiety disorder in a subject, comprising administering to thesubject an effective amount of a compound described herein (e.g., acompound of the Formula (I), Formula (II), Formula (III), or Formula(IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

In an aspect, provided herein is a method for treating disorders relatedto GABA function in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound, a pharmaceutically acceptable salt thereof, or pharmaceuticalcomposition of a compound described herein (e.g., a compound of theFormula (I), Formula (II), Formula (III), or Formula (IV), Formula(1-A), Formula (2-A), or Formula (3-A)).

In an aspect, provided herein is a kit comprising a solid compositioncomprising a compound described herein (e.g., a compound of the Formula(I), Formula (II), Formula (III), or Formula (IV), Formula (1-A),Formula (2-A), or Formula (3-A)) and a sterile diluent.

Thus, in another aspect, provided are methods of treating a CNS-relateddisorder in a subject in need thereof, comprising administering to thesubject an effective amount of a compound as described herein (e.g., acompound of the Formula (I), Formula (II), Formula (III), or Formula(IV), Formula (1-A), Formula (2-A), or Formula (3-A)). In certainembodiments, the CNS-related disorder is selected from the groupconsisting of a sleep disorder, a mood disorder, a schizophreniaspectrum disorder, a convulsive disorder, a disorder of memory and/orcognition, a movement disorder, a personality disorder, autism spectrumdisorder, pain, traumatic brain injury, a vascular disease, a substanceabuse disorder and/or withdrawal syndrome, and tinnitus. In certainembodiments, the compound is administered orally, subcutaneously,intravenously, or intramuscularly. In certain embodiments, the compoundis administered chronically. In certain embodiments, the compound isadministered continuously, e.g., by continuous intravenous infusion.

In some embodiments, the subject is a subject with Rett syndrome,Fragile X syndrome, or Angelman syndrome.

Definitions Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Isomers can be isolated from mixtures by methods known to those skilledin the art, including chiral high pressure liquid chromatography (HPLC)and the formation and crystallization of chiral salts; or preferredisomers can be prepared by asymmetric syntheses. See, for example,Jacques et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); andWilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L.Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972). Theinvention additionally encompasses compounds described herein asindividual isomers substantially free of other isomers, andalternatively, as mixtures of various isomers.

The absolute configuration of an asymmetric center can be determinedusing methods known to one skilled in the art. In some embodiments, theabsolute configuration of an asymmetric center in a compound can beelucidated from the X-ray single-crystal structure of the compound. Insome embodiments, the absolute configuration of an asymmetric centerelucidated by the X-ray crystal structure of a compound can be used toinfer the absolute configuration of a corresponding asymmetric center inanother compound obtained from the same or similar syntheticmethodologies. In some embodiments, absolute configuration of anasymmetric center can be determined using nuclear Overhauser effect(NOE) experiments via nuclear magnetic resonance (NMR) spectroscopy.

In some embodiments, an asymmetric center of known absoluteconfiguration can be introduced into a compound with a chiral reactant,e.g., a chiral amine. In some embodiments, an asymmetric center of knownabsolute configuration can be introduced into a compound with a reactionmethodology, e.g., by a reductive amination.

As used herein a pure enantiomeric compound is substantially free fromother enantiomers or stereoisomers of the compound (i.e., inenantiomeric excess). In other words, an “S” form of the compound issubstantially free from the “R” form of the compound and is, thus, inenantiomeric excess of the “R” form. The term “enantiomerically pure” or“pure enantiomer” denotes that the compound comprises more than 75% byweight, more than 80% by weight, more than 85% by weight, more than 90%by weight, more than 91% by weight, more than 92% by weight, more than93% by weight, more than 94% by weight, more than 95% by weight, morethan 96% by weight, more than 97% by weight, more than 98% by weight,more than 98.5% by weight, more than 99% by weight, more than 99.2% byweight, more than 99.5% by weight, more than 99.6% by weight, more than99.7% by weight, more than 99.8% by weight or more than 99.9% by weight,of the enantiomer. In certain embodiments, the weights are based upontotal weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, an enantiomerically pure compoundcan be present with other active or inactive ingredients. For example, apharmaceutical composition comprising enantiomerically pure R-compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure R-compound. In certain embodiments, theenantiomerically pure R-compound in such compositions can, for example,comprise, at least about 95% by weight R-compound and at most about 5%by weight S-compound, by total weight of the compound. For example, apharmaceutical composition comprising enantiomerically pure S-compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure S-compound. In certain embodiments, theenantiomerically pure S-compound in such compositions can, for example,comprise, at least about 95% by weight S-compound and at most about 5%by weight R-compound, by total weight of the compound. In certainembodiments, the active ingredient can be formulated with little or noexcipient or carrier.

The articles “a” and “an” may be used herein to refer to one or to morethan one (i.e. at least one) of the grammatical objects of the article.By way of example “an analogue” means one analogue or more than oneanalogue.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₁₋₆ alkyl.

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 12 carbon atoms (“C₁₋₁₂alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms(“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 6 carbonatoms (“C₁₋₆ alkyl”, also referred to herein as “lower alkyl”). In someembodiments, an alkyl group has 1 to 5 carbon atoms (“C₁₋₅ alkyl”). Insome embodiments, an alkyl group has 1 to 4 carbon atoms (“C₁₋₄ alkyl”).In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C₁₋₃alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms(“C₁₋₂ alkyl”). In some embodiments, an alkyl group has 1 carbon atom(“C₁ alkyl”). In some embodiments, an alkyl group has 2 to 6 carbonatoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groups include methyl (C₁),ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl(C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅), 3-pentanyl (C₅),amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅),and n-hexyl (C₆). Additional examples of alkyl groups include n-heptyl(C₇), n-octyl (C₈) and the like. Unless otherwise specified, eachinstance of an alkyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a“substituted alkyl”) with one or more substituents; e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkyl group is unsubstituted C₁₋₁₀ alkyl (e.g.,—CH₃). In certain embodiments, the alkyl group is substituted C₁₋₁₀alkyl. Common alkyl abbreviations include Me (—CH₃), Et (—CH₂CH₃), iPr(—CH(CH₃)₂), nPr (—CH₂CH₂CH₃), n-Bu (—CH₂CH₂CH₂CH₃), or i-Bu(—CH₂CH(CH₃)₂).

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds, and no triple bonds (“C₂₋₂₀ alkenyl”). Insome embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms(“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has 2 to 6carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, an alkenyl group has2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In some embodiments, an alkenylgroup has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”). In some embodiments, analkenyl group has 2 to 3 carbon atoms (“C₂₋₃ alkenyl”). In someembodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The oneor more carbon-carbon double bonds can be internal (such as in2-butenyl) or terminal (such as in 1-butenyl). Examples of C₂₋₄ alkenylgroups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl(C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C₂₋₆alkenyl groups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₈), hexenyl (C₆), and the like. Additionalexamples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl(C₈), and the like. Unless otherwise specified, each instance of analkenyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl.In certain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds, and optionally one or more double bonds(“C₂₋₂₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 10carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, analkynyl group has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In someembodiments, an alkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”).In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms(“C₂₋₃ alkynyl”). In some embodiments, an alkynyl group has 2 carbonatoms (“C₂ alkynyl”). The one or more carbon-carbon triple bonds can beinternal (such as in 2-butynyl) or terminal (such as in 1-butynyl).Examples of C₂₋₄ alkynyl groups include, without limitation, ethynyl(C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄),and the like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like. Unless otherwise specified, each instance of analkynyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents; e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 πelectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₋₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Arylgroups include, but are not limited to, phenyl, naphthyl, indenyl, andtetrahydronaphthyl. Unless otherwise specified, each instance of an arylgroup is independently optionally substituted, i.e., unsubstituted (an“unsubstituted aryl”) or substituted (a “substituted aryl”) with one ormore substituents. In certain embodiments, the aryl group isunsubstituted C₆₋₁₄ aryl. In certain embodiments, the aryl group issubstituted C₆₋₁₄ aryl.

In certain embodiments, an aryl group substituted with one or more ofgroups selected from halo, C₁-C₈ alkyl, C₁-C₈ haloalkyl, cyano, hydroxy,C₁-C₈ alkoxy, and amino.

Examples of representative substituted aryls include the following

wherein one of R⁵⁶ and R⁵⁷ may be hydrogen and at least one of R⁵⁶ andR⁵¹ is each independently selected from C₁-C₈ alkyl, C₁-C₈ haloalkyl,4-10 membered heterocyclyl, alkanoyl, C₁-C₈ alkoxy, heteroaryloxy,alkylamino, arylamino, heteroarylamino, NR⁵⁸COR⁵⁹, NR⁵⁸SOR⁵⁹NR⁵⁸SO₂R⁵⁹,COOalkyl, COOaryl, CONR⁵⁸R⁵⁹, CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹, SO₂NR⁵⁸R⁵⁹, S-alkyl,SOalkyl, SO₂alkyl, Saryl, SOaryl, SO₂aryl; or R⁵⁶ and R⁵⁷ may be joinedto form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms,optionally containing one or more heteroatoms selected from the group N,O, or S. R⁶⁰ and R⁶¹ are independently hydrogen, C₁-C₈ alkyl, C₁-C₄haloalkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,substituted C₆-C₁₀ aryl, 5-10 membered heteroaryl, or substituted 5-10membered heteroaryl.

Other representative aryl groups having a fused heterocyclyl groupinclude the following:

wherein each W is selected from C(R⁶⁶)₂, NR⁶⁶, O, and S; and each Y isselected from carbonyl, NR⁶⁶, O and S; and R⁶⁶ is independentlyhydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl,C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

“Halo” or “halogen,” independently or as part of another substituent,mean, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine(Br), or iodine (I) atom. The term “halide” by itself or as part ofanother substituent, refers to a fluoride, chloride, bromide, or iodideatom. In certain embodiments, the halo group is either fluorine orchlorine.

“Haloalkyl” and “haloalkoxy” can include alkyl and alkoxy structuresthat are substituted with one or more halo groups or with combinationsthereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” includehaloalkyl and haloalkoxy groups, respectively, in which the halo isfluorine.

“Hydroxy” or “hydroxyl,” independently or as part of anothersubstituent, mean, unless otherwise stated, a —OH group.

Hydroxyalkyl” or “hydroxylalkyl” can include alkyl structures that aresubstituted with one or more hydroxyl groups.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or □□□□ electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following formulae:

wherein each Y is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ isindependently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃_6 carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged or spiro ring systemsuch as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

Particular examples of heterocyclyl groups are shown in the followingillustrative examples:

wherein each W is selected from CR⁶⁷, C(R⁶⁷)₂, NR⁶⁷, O, and S; and eachY is selected from NR⁶⁷, O, and S; and R⁶⁷ is independently hydrogen,C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,and 5-10-membered heteroaryl. These heterocyclyl rings may be optionallysubstituted with one or more groups selected from the group consistingof acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (e.g.,amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro,thiol, —S-alkyl, —S-aryl, —S(O)-alkyl, —S(O)-aryl, —S(O)₂-alkyl, and—S(O)₂-aryl. Substituting groups include carbonyl or thiocarbonyl whichprovide, for example, lactam and urea derivatives.

“Acyl” refers to a radical —C(O)R²⁰, where R²⁰ is hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, asdefined herein. “Alkanoyl” is an acyl group wherein R²⁰ is a group otherthan hydrogen. Representative acyl groups include, but are not limitedto, formyl (—CHO), acetyl (—C(═O)CH₃), cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl (—C(═O)Ph), benzylcarbonyl(—C(═O)CH₂Ph), —C(O)—C₁-C₈ alkyl, —C(O)—(CH₂)_(t)(C₆-C₁₀ aryl),—C(O)—(CH₂)_(t)(5-membered heteroaryl), —C(O)—(CH₂)_(t)(C₃-C₁₀cycloalkyl), and —C(O)—(CH₂)_(t)(4-10 membered heterocyclyl), wherein tis an integer from 0 to 4. In certain embodiments, R²¹ is C₁-C₈ alkyl,substituted with halo or hydroxy; or C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, arylalkyl, 5-10 membered heteroaryl orheteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy.

“Acylamino” refers to a radical —NR²²C(O)R²³, where each instance of R²²and R²³ is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, as defined herein, or R²² is anamino protecting group. Exemplary “acylamino” groups include, but arenot limited to, formylamino, acetylamino, cyclohexylcarbonylamino,cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino.Particular exemplary “acylamino” groups are —NR²⁴C(O)—C₁-C₈ alkyl,—NR²⁴C(O)—(CH₂)_(t)(C₆-C₁₀ aryl), —NR²⁴C(O)—(CH₂)_(t)(5-10 memberedheteroaryl), —NR²⁴C(O)—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and—NR²⁴C(O)—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integerfrom 0 to 4, and each R²⁴ independently represents hydrogen or C₁-C₈alkyl. In certain embodiments, R²⁵ is H, C₁-C₈ alkyl, substituted withhalo or hydroxy; C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each ofwhich is substituted with unsubstituted C₁-C₄ alkyl, halo, unsubstitutedC₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy or hydroxy; and R²⁶ isH, C₁-C₈ alkyl, substituted with halo or hydroxy; C₃-C₁₀ cycloalkyl,4-10-membered heterocyclyl, C₆-C₁₀ aryl, arylalkyl, 5-10-memberedheteroaryl or heteroarylalkyl, each of which is substituted withunsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄ alkoxy,unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl, orunsubstituted C₁-C₄ haloalkoxy or hydroxy; provided at least one of R²⁵and R²⁶ is other than H.

“Acyloxy” refers to a radical —OC(O)R²⁷, where R²⁷ is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl, as defined herein. Representative examples include, but arenot limited to, formyl, acetyl, cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, and benzylcarbonyl. In certainembodiments, R²⁸ is C₁-C₈ alkyl, substituted with halo or hydroxy;C₃-C₁₀ cycloalkyl, 4-10-membered heterocyclyl, C₆-C₁₀ aryl, arylalkyl,5-10-membered heteroaryl or heteroarylalkyl, each of which issubstituted with unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy.

“Alkoxy” refers to the group —OR²⁹ where R²⁹ is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl. Particular alkoxygroups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.Particular alkoxy groups are lower alkoxy, i.e., with between 1 and 6carbon atoms. Further particular alkoxy groups have between 1 and 4carbon atoms.

In certain embodiments, R²⁹ is a group that has 1 or more substituents,for instance from 1 to 5 substituents, and particularly from 1 to 3substituents, in particular 1 substituent, selected from the groupconsisting of amino, substituted amino, C₆-C₁₀ aryl, aryloxy, carboxyl,cyano, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10membered heteroaryl, hydroxy, nitro, thioalkoxy, thioaryloxy, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—. Exemplary“substituted alkoxy” groups include, but are not limited to,—O—(CH₂)_(t)(C₆-C₁₀ aryl), —O—(CH₂)_(t)(5-10 membered heteroaryl),—O—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and —O—(CH₂)_(t)(4-10 memberedheterocyclyl), wherein t is an integer from 0 to 4 and any aryl,heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves besubstituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. Particular exemplary‘substituted alkoxy’ groups are —OCF₃, —OCH₂CF₃, —OCH₂Ph,—OCH₂-cyclopropyl, —OCH₂CH₂OH, and —OCH₂CH₂NMe₂.

“Amino” refers to the radical —NH₂.

“Oxo” refers to ═O.

“Substituted amino” refers to an amino group of the formula —N(R³⁸)₂wherein R³⁸ is hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or an amino protecting group, wherein at leastone of R³⁸ is not a hydrogen. In certain embodiments, each R³⁸ isindependently selected from hydrogen, C₁-C₈ alkyl, C₃-C₈ alkenyl, C₃-C₈alkynyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, 4-10 memberedheterocyclyl, or C₃-C₁₀ cycloalkyl; or C₁-C₈ alkyl, substituted withhalo or hydroxy; C₃-C₈ alkenyl, substituted with halo or hydroxy; C₃-C₈alkynyl, substituted with halo or hydroxy, or —(CH₂)_(t)(C₆-C₁₀ aryl),—(CH₂)_(t)(5-10 membered heteroaryl), —(CH₂)_(t)(C₃-C₁₀ cycloalkyl), or—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integer between0 and 8, each of which is substituted by unsubstituted C₁-C₄ alkyl,halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy; or both R³⁸ groups are joined to form an alkylene group.

Exemplary “substituted amino” groups include, but are not limited to,—NR³⁹—C₁-C₈ alkyl, —NR³⁹—(CH₂)_(t)(C₆-C₁₀ aryl), —NR³⁹—(CH₂)_(t)(5-10membered heteroaryl), —NR³⁹—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and—NR³⁹—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integerfrom 0 to 4, for instance 1 or 2, each R³⁹ independently representshydrogen or C₁-C₈ alkyl; and any alkyl groups present, may themselves besubstituted by halo, substituted or unsubstituted amino, or hydroxy; andany aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, maythemselves be substituted by unsubstituted C₁-C₄ alkyl, halo,unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstitutedC₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy or hydroxy. Forthe avoidance of doubt the term ‘substituted amino’ includes the groupsalkylamino, substituted alkylamino, alkylarylamino, substitutedalkylarylamino, arylamino, substituted arylamino, dialkylamino, andsubstituted dialkylamino as defined below. Substituted amino encompassesboth monosubstituted amino and disubstituted amino groups.

“Azido” refers to the radical —N₃.

“Carbamoyl” or “amido” refers to the radical —C(O)NH₂.

“Substituted carbamoyl” or “substituted amido” refers to the radical—C(O)N(R⁶²)₂ wherein each R⁶² is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, or an amino protectinggroup, wherein at least one of R⁶² is not a hydrogen. In certainembodiments, R⁶² is selected from H, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl,4-10 membered heterocyclyl, C₆-C₁₀ aryl, and 5-membered heteroaryl; orC₁-C₈ alkyl substituted with halo or hydroxy; or C₃-C₁₀ cycloalkyl, 4-10membered heterocyclyl, C₆-C₁₀ aryl, or 5-10 membered heteroaryl, each ofwhich is substituted by unsubstituted C₁-C₄ alkyl, halo, unsubstitutedC₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy or hydroxy; providedthat at least one R⁶² is other than H.

“Carboxy” refers to the radical —C(O)OH.

“Cyano” refers to the radical —CN.

“Nitro” refers to the radical —NO₂.

“Ethenyl” refers to substituted or unsubstituted —(C═C)—. “Ethylene”refers to substituted or unsubstituted —(C—C)—. “Ethynyl” refers to—(C≡C)—.

“Nitrogen-containing heterocyclyl” group means a 4- to 7-memberednon-aromatic cyclic group containing at least one nitrogen atom, forexample, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline,imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methyl piperazine. Particular examples includeazetidine, piperidone and piperazone.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that results in theformation of a stable compound. The present invention contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this invention, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, N(R^(bb))₃ ⁺X⁻, —N(OR^(cc)R^(bb), —SH, —SR^(aa), —SSR^(cc),—C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa), —OC(═O)R^(aa),—OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂, —NR^(bb)C(═O)R^(aa),—NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa),—C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(aa) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of Re is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two Reb groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 Rad groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 Rad groups;

each instance of Rad is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R¹ is, independently, halogen, —CN, —NO₂, —N₃, —SO₂H,—SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂, —N(C₁₋₆alkyl)₃X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl) ⁺X⁻, —NH₃X⁻, —N(OC₁₋₆alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl,—SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl),—OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂,—OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl),—OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl),—C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂,—NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl,—OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl),—P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl;wherein X⁻ is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like).

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substitutents include, but are not limited to,hydrogen, —OH, —OR^(aa), N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14-memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14-membered heterocyclyl or 5-14-membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined above.

In certain embodiments, the substituent present on a nitrogen atom is anamino protecting group (also referred to herein as a nitrogen protectinggroup). Amino protecting groups include, but are not limited to, —OH,—OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)OR^(aa), —C(═O)N(R^(cc))₂,—S(═O)₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14-memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14-membered heteroaryl groups, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are as definedherein. Amino protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

Exemplary amino protecting groups include, but are not limited to amidegroups (e.g., —C(═O)R^(aa)), which include, but are not limited to,formamide and acetamide; carbamate groups (e.g., —C(═O)OR^(aa)), whichinclude, but are not limited to, 9-fluorenylmethyl carbamate (Fmoc),t-butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups(e.g., —S(═O)₂R^(aa)), which include, but are not limited to,p-toluenesulfonamide (Ts), methanesulfonamide (Ms), andN-[2-(trimethylsilyl)ethoxy]methylamine (SEM).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to as a hydroxyl protectinggroup). Oxygen protecting groups include, but are not limited to,—R^(aa), —N(Reb)₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(Reb)₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa),—Si(R^(aa))₃—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn),triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS),t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), andtosylate (Ts).

In certain embodiments, the substituent present on an sulfur atom is ansulfur protecting group (also referred to as a thiol protecting group).Sulfur protecting groups include, but are not limited to, —R^(aa),—N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(Reb)₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃—P(R^(cc))₂, —P(R^(cc))₃,—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(Reb)₂, and—P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. Sulfur protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and Claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other Definitions

As used herein, the term “modulation” refers to the inhibition orpotentiation of GABA receptor function. A “modulator” (e.g., a modulatorcompound) may be, for example, an agonist, partial agonist, antagonist,or partial antagonist of the GABA receptor.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly, in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like. The term“pharmaceutically acceptable cation” refers to an acceptable cationiccounter-ion of an acidic functional group. Such cations are exemplifiedby sodium, potassium, calcium, magnesium, ammonium, tetraalkylammoniumcations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977)66(1): 1-79.

“Solvate” refers to forms of the compound that are associated with asolvent or water (also referred to as “hydrate”), usually by asolvolysis reaction. This physical association includes hydrogenbonding. Conventional solvents include water, ethanol, acetic acid, andthe like. The compounds of the invention may be prepared e.g. incrystalline form and may be solvated or hydrated. Suitable solvatesinclude pharmaceutically acceptable solvates, such as hydrates, andfurther include both stoichiometric solvates and non-stoichiometricsolvates. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Representative solvates includehydrates, ethanolates and methanolates.

“Stereoisomers”: It is also to be understood that compounds that havethe same molecular formula but differ in the nature or sequence ofbonding of their atoms or the arrangement of their atoms in space aretermed “isomers.” Isomers that differ in the arrangement of their atomsin space are termed “stereoisomers.” Stereoisomers that are not mirrorimages of one another are termed “diastereomers” and those that arenon-superimposable mirror images of each other are termed “enantiomers.”When a compound has an asymmetric center, for example, it is bonded tofour different groups, a pair of enantiomers is possible. An enantiomercan be characterized by the absolute configuration of its asymmetriccenter and is described by the R- and S-sequencing rules of Cahn andPrelog, or by the manner in which the molecule rotates the plane ofpolarized light and designated as dextrorotatory or levorotatory (i.e.,as (+) or (−)-isomers respectively). A chiral compound can exist aseither individual enantiomer or as a mixture thereof. A mixturecontaining equal proportions of the enantiomers is called a “racemicmixture”.

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of 7 electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenylnitromethane, that arelikewise formed by treatment with acid or base. Tautomeric forms may berelevant to the attainment of the optimal chemical reactivity andbiological activity of a compound of interest.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats, and/or dogs. In certain embodiments, the subject is a human. Incertain embodiments, the subject is a non-human animal. The terms“human,” “patient,” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition (“prophylactic treatment”).

In general, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response, e.g., to treat aCNS-related disorder, is sufficient to induce anesthesia or sedation. Aswill be appreciated by those of ordinary skill in this art, theeffective amount of a compound of the invention may vary depending onsuch factors as the desired biological endpoint, the pharmacokinetics ofthe compound, the disease being treated, the mode of administration, andthe age, weight, health, and condition of the subject. An effectiveamount encompasses therapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease, disorder or condition, or one or more symptoms associated withthe disease, disorder or condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease,disorder or condition. The term “prophylactically effective amount” canencompass an amount that improves overall prophylaxis or enhances theprophylactic efficacy of another prophylactic agent.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

Provided herein are compounds (e.g., compound of Formula (I)),pharmaceutical compositions, and their methods of use to treat a diseaseor disorder as described herein.

Compounds

Compounds described herein are generally designed to modulate GABAfunction, and therefore to act as neuroactive steroids for the treatmentand prevention of CNS-related conditions in a subject. Modulation, asused herein, refers to the inhibition or potentiation of GABA receptorfunction. Accordingly, the compounds and pharmaceutical compositionsprovided herein find use as therapeutics for preventing and/or treatingCNS conditions in mammals including humans and non-human mammals. Thus,and as stated earlier, the present invention includes within its scope,and extends to, the recited methods of treatment, as well as to thecompounds for such methods, and to the use of such compounds for thepreparation of medicaments useful for such methods.

In an aspect, provided herein is a compound of the Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: each of R², R⁴,R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen, halogen, cyano,nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, NHC(═O)R^(A1),—S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), wherein each instance ofR^(A1) is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attachedto an oxygen atom, a sulfur protecting group when attached to a sulfuratom, a nitrogen protecting group when attached to a nitrogen atom, ortwo R^(A1) groups are joined to form an heterocyclic or heteroaryl ring;and R^(A2) is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,or heteroaryl; or R^(11a) and R^(11b) together with the carbon atom towhich they are attached form a carbocyclyl, heterocyclyl, or —C(═O)—; R³is hydrogen, alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl; each of R^(11a) and Rim is independently hydrogen, halogen,cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1),—S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), wherein at least one ofR^(17a) and R^(17b) is not hydrogen; R¹⁹ is hydrogen or alkyl (e.g.,unsubstituted alkyl or substituted alkyl (e.g., —C(R^(C))₂OR^(A1),wherein R^(C) is hydrogen or alkyl)); R⁵ is absent or hydrogen; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent.

In some embodiments, R¹⁹ is hydrogen or alkyl. In some embodiments, R¹⁹is unsubstituted alkyl. In some embodiments, R¹⁹ is substituted alkyl.In some embodiments, R¹⁹ is —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, or—CH₂OCH(CH₃)₂.

In some embodiments, R² is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R² is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R² is hydrogen.

In some embodiments, R³ is alkyl, alkenyl, carbocyclyl, heterocyclyl,aryl, or heteroaryl. In some embodiments, R³ is alkyl (e.g., substitutedor unsubstituted alkyl), alkenyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl. In some embodiments, R³ is methyl and ethyl (e.g.,substituted or unsubstituted alkyl).

In some embodiments, R⁴ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁴ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁴ is hydrogen.

In some embodiments,

represents a single bond and R⁵ is hydrogen. In some embodiments, R⁵ isabsent, and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond.

In some embodiments, R⁶ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁶ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁶ is hydrogen.

In some embodiments, R⁷ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁷ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁷ is hydrogen.

In some embodiments, R^(11a) is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, orR^(11a) and R^(11b) together with the carbon atom to which they areattached form —C(═O)—. In some embodiments, R^(11a) is hydrogen,halogen, alkyl, or —OR^(A1). In some embodiments, R^(11a) and R^(11b)together with the carbon atom to which they are attached form —C(═O)—.In some embodiments, R^(11a) and R^(11b) are hydrogen.

In some embodiments, each of R², R⁴, R⁶, R⁷, R^(11a), and R^(11b) isindependently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. In some embodiments,each of R², R⁴, R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen,halogen, alkyl, or —OR^(A1). In some embodiments, R², R⁴, R⁶, R⁷,R^(11a), and R^(11b) are hydrogen.

In some embodiments, each of R^(17a) and R^(17b) is independentlyhydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, —SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1)—S(═O)R^(A2),—SO₂R^(A2) or —S(═O)₂OR^(A1), wherein at least one of R^(17a) andR^(17b) is not hydrogen. In some embodiments, each of R^(17a) andR^(17b) is independently hydrogen, halogen, nitro, alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, —SR^(A1), —N(R^(A1))₂,—NHC(═O)R^(A1)—S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), wherein atleast one of R^(17a) and R^(17b) is not hydrogen.

In some embodiments, R^(17a) is halogen, cyano, nitro, alkyl,carbocyclyl, heterocyclyl, —OR^(A1), —SR^(A1), —N(R^(A1))₂,—NHC(═O)R^(A1), —S(═O)R^(A2), or —SO₂Re. In some embodiments, R^(11a) ishalogen, nitro, alkyl, carbocyclyl, heterocyclyl, —OR^(A1), —SR^(A1),—N(R^(A1))₂, —NHC(═O)R^(A1), —S(═O)R^(A2), or —SO₂R^(A2). In someembodiments, R^(11a) is halogen, cyano, nitro, alkyl, —OR^(A1),—SR^(A1), or —N(R^(A1))₂.

In some embodiments, the compound is:

or a pharmaceutically acceptable salt thereof.

In an aspect, provided herein is a compound of the Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: each of R², R⁴,R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen, halogen, cyano,nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), whereineach instance of R^(A1) is independently hydrogen, alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygenprotecting group when attached to an oxygen atom, a sulfur protectinggroup when attached to a sulfur atom, a nitrogen protecting group whenattached to a nitrogen atom, or two R^(A1) groups are joined to form anheterocyclic or heteroaryl ring; and R^(A2) is alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R^(11a) and R^(11b)together with the carbon atom to which they are attached form acarbocyclyl, heterocyclyl, or —C(═O)— group; R³ is hydrogen, alkyl,alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; A is alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, —OR^(A1), —SR^(A1), or—N(R^(A1))₂; R¹⁹ is hydrogen or alkyl (e.g., unsubstituted alkyl (e.g.,—CH₃) or substituted alkyl (e.g., —C(R^(C))₂OR^(A1), wherein R^(C) ishydrogen or alkyl)); R⁵ is absent or hydrogen; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent.

In some embodiments, A is hydrogen, alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, or —OR^(A1).

In some embodiments, R¹⁹ is hydrogen. In some embodiments, R¹⁹ is alkyl(e.g., substituted or unsubstituted alkyl). In some embodiments, R¹⁹ is—CH₃ or —CH₂CH₃. In some embodiments, R¹⁹ is —C(R^(C))₂OR^(A1). In someembodiments, R¹⁹ is —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, or —CH₂OCH(CH₃)₂.

In some embodiments, R² is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R² is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R² is hydrogen.

In some embodiments, R³ is alkyl (e.g., substituted or unsubstitutedalkyl). In some embodiments, R³ is methyl and ethyl (e.g., substitutedor unsubstituted methyl, substituted or unsubstituted ethyl).

In some embodiments, R⁴ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁴ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁴ is hydrogen.

In some embodiments,

represents a single bond and R⁵ is hydrogen. In some embodiments, R⁵ isabsent, and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond.

In some embodiments, R⁶ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁶ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁶ is hydrogen.

In some embodiments, R⁷ is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. Insome embodiments, R⁷ is hydrogen, halogen, alkyl, or —OR^(A1). In someembodiments, R⁷ is hydrogen.

In some embodiments, R^(11a) is hydrogen, halogen, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, orR^(11a) and R^(11b) together with the carbon atom to which they areattached form —C(═O)—. In some embodiments, R^(11a) is hydrogen,halogen, alkyl, or —OR^(A1). In some embodiments, R^(11a) and R^(11b)together with the carbon atom to which they are attached form —C(═O)—.In some embodiments, R^(11a) and R^(11b) are hydrogen.

In some embodiments, each of R², R⁴, R⁶, R⁷, R^(11a), and R^(11b) isindependently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂. In some embodiments,each of R², R⁴, R⁶, R⁷, R^(11a), and R^(11b) is hydrogen, halogen,alkyl, or —OR^(A1). In some embodiments, each of R², R⁴, R⁶, R⁷,R^(11a), and R^(11b) is hydrogen.

In some embodiments, the compound of Formula (II) is a compound of theFormula (II-a) or (II-b):

In some embodiments, the compound of Formula (I) is a compound of theFormula (II-c):

wherein:each of R^(11a) and R^(21b) is independently hydrogen, halogen, cyano,nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1); or R^(11a)and R^(21b) together with the carbon atom to which they are attachedform a carbocyclyl, heterocyclyl, or —C(═O)— group; Q is hydrogen,halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, —OR^(A1), —SR^(A1), or —N(R^(A1))₂; andn is an integer selected from 1, 2, and 3.

In some embodiments, the compound of Formula (II) is a compound of theFormula (II-d):

In an aspect, provided herein is a compound of the Formula (III-a):

or a pharmaceutically acceptable salt thereof, wherein: each of R², R⁴,R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen, halogen, cyano,nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), whereineach instance of R^(A1) is independently hydrogen, alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygenprotecting group when attached to an oxygen atom, a sulfur protectinggroup when attached to a sulfur atom, a nitrogen protecting group whenattached to a nitrogen atom, or two R^(A1) groups are joined to form anheterocyclic or heteroaryl ring; and R^(A2) is alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R^(11a) and R^(11b)together with the carbon atom to which they are attached form acarbocyclyl, heterocyclyl, or —C(═O)— group; Q is hydrogen, halogen,cyano, nitro, alkyl, alkenyl, alkynyl, —OR^(A1), —SR^(A1), or—N(R^(A1))₂; R¹⁹ is unsubstituted alkyl; R⁵ is absent or hydrogen; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent.

In an aspect, provided herein is a compound of the Formula (III-b):

or a pharmaceutically acceptable salt thereof, wherein: each of R², R⁴,R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen, halogen, cyano,nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), whereineach instance of R^(A1) is independently hydrogen, alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygenprotecting group when attached to an oxygen atom, a sulfur protectinggroup when attached to a sulfur atom, a nitrogen protecting group whenattached to a nitrogen atom, or two R^(A1) groups are joined to form anheterocyclic or heteroaryl ring; and R^(A2) is alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R^(11a) and R^(11b)together with the carbon atom to which they are attached form acarbocyclyl, heterocyclyl, or —C(═O)— group; R³ is alkyl, alkenyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl; Q is halogen, cyano,nitro, heterocyclyl linked through a C atom, aryl, heteroaryl linkedthrough a C atom, —O-alkenyl, —O-alkynyl, —SR^(A1), —N(R^(A1))₂,—NHC(═O)R^(A1), —NHC(═O)OR^(A1), —S(═O)R^(A1), —SO₂R^(A1), or—S(═O)₂OR^(A1); R¹⁹ is —C(R^(C))₂OR^(A1) wherein R^(C) is hydrogen oralkyl; R⁵ is absent or hydrogen; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent.

In an aspect, provided herein is a compound of Formula (1-A):

or a pharmaceutically acceptable salt thereof, wherein: R³ is alkyl,alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each of R^(X)and R^(Y) is independently hydrogen, aryl, or alkyl, orR^(X) and R^(Y) are joined together to form a 3-10 membered heterocyclicring; R¹⁹ is hydrogen or alkyl (e.g., unsubstituted alkyl or substitutedalky (e.g., —C(R^(C))₂OR^(A1), wherein R^(C) is hydrogen or alkyl)); R⁵is absent or hydrogen;

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁸ is absent; and a is 0 or 1; provided that R^(X)and R^(Y) are joined togethe

a 3-8 membered heterocyclic ring only when a is 0.

In some embodiments, R^(X) and R^(Y) are not both hydrogen. In someembodiments, R³ is alkyl. In some embodiments, R¹⁹ is hydrogen.

In some embodiments, the compound is a compound of Formula (1-A-1)

wherein each instance of R^(Y4) is independently alkyl, cyano, or halo;and e is 0, 1, 2, 3, 4, or 5.

In some embodiments, each instance of R^(Y4) is independently hydrogen,—CH₃, —CN, or —F. In some embodiments, e is 3. In some embodiments,R^(X) is hydrogen. In some embodiments, each instance of R^(Y4) isindependently hydrogen, —CH₃, —CN, or —F, R^(X) is hydrogen, and e is 3.In some embodiments, each instance of R^(Y4) is independently hydrogen,—CH₃, —CN, or —F, R^(X) is hydrogen, and e is 2. In some embodiments, eis 1. In some embodiments, R^(Y4) is —F. In some embodiments, R^(Y4) is—F and e is 1.

In some embodiments, the compound is a compound of Formula (1-A-2)

In some embodiments, each instance of R^(Y4) is independently hydrogen,—CH₃, —CN, or —F. In some embodiments, e is 3. In some embodiments,R^(X) is hydrogen. In some embodiments, each instance of R^(Y4) isindependently hydrogen, —CH₃, —CN, or —F, R^(X) is hydrogen, and e is 3.In some embodiments, each instance of R^(Y4) is independently hydrogen,—CH₃, —CN, or —F, R^(X) is hydrogen, and e is 2. In some embodiments, eis 1. In some embodiments, R^(Y4) is —F.

In some embodiments, the compound is a compound of Formula (1-A-3)

wherein each of R^(Y1) and R^(Y2) is independently alkyl, cycloalkyl,heterocycyl, aryl, or heteroaryl; and b=0, 1, 2, 3.

In some embodiments, R^(Y1) and R^(Y2) are not both —CH(CH₃)₂.

In some embodiments, the compound is a compound of Formula (1-A-4)

In some embodiments, R^(Y1) is hydrogen, —CH₃, or —CH₂CH₃, —CH(CH₃)₂, orcycloalkyl.

In some embodiments, R³ is —CH₃, —CF₃, —CH₂OCH₃, —CH₂OCH₂CH₃. In someembodiments, R^(Y2) is heteocyclyl, aryl, or heteroaryl. In someembodiments, R^(Y2) is aryl substituted with 0-5 occurrences of —CH₃,—CN, —F, —CF₃, or combinations thereof or heteroaryl substituted with0-5 occurrences of —CH₃, —CN, —F, —CF₃.

In some embodiments, R^(Y2) is aryl substituted with 0-5 occurrences of—CH₃, —CN, —F, —CF₃, or R^(X) is hydrogen, —CH₃, or —CH₂CH₃. In someembodiments, R is aryl substituted with 0-5 occurrences of —CH₃, —CN,—F, —CF₃.

In some embodiments, the compound is a compound of Formula (1-A-5)

wherein each occurrence of R^(Y3) is aryl or heteroaryl, or two R^(Y3)groups are joined together to form a 6-membered ring;

c is 0, 1, 2, or 3; and

d is 0, 1, 2, or 3.

In some embodiments, the compound is a compound of Formula (1-A-6)

In some embodiments, if d is 2, then two R³ groups are joined togetherto form aryl. In some embodiments, R^(Y2) is aryl substituted with 0-5occurrences of —CH₃, —CN, —F, —CF₃. In some embodiments, the compound isa compound of Formula (1-A-7) or Formula (1-A-8)

In some embodiments, R^(Y2) is aryl substituted with 0-5 occurrences of—CH₃, —CN, —F, —CF₃, or R³ is —CH₃, —CF₃, —CH₂OCH₃, —CH₂OCH₂CH₃.

In an aspect, provided herein is a compound of Formula (2-A),

or a pharmaceutically acceptable salt thereof, wherein R³ is —CH₃, —CF₃,—CH₂OCH₃, —CH₂OCH₂CH₃; R¹⁹ is hydrogen, —CH₃, or —CH₂OR^(A1), whereinR^(A1) is optionally substituted alkyl; R³ is —CH₃, —CF₃, —CH₂OCH₃,—CH₂OCH₂CH₃; R^(17a) is NR^(A2)R^(A3), —N(R¹)C(O)Re, —N(R¹)SO₂R^(A2),—OR^(A3), cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each ofR^(A2) and R^(A3) is independently hydrogen, carbocyclyl, heterocyclyl,aryl, heteroaryl, or —OR^(A4), wherein R^(A4) is hydrogen or alkyl; orR^(17A) is

wherein A is oxazolyl or thiazolyl; R^(17b) is hydrogen, hydroxyl,alkyl, or alkoxy; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent; provided that: when R^(17a) isoxazolyl or,

then R^(17b) is not hydrogen, or when R^(17a) is heterocyclyl, then R¹⁹is hydrogen, or when R^(17a) is —OR^(A4), then R¹⁹ is hydrogen.

In some embodiments, R^(17a) is —NR^(A2)R^(A3), —N(R1)C(O)R^(A2),—N(R1)SO₂R^(A2). In some embodiments, R^(17a) is aryl, heteroaryl,cycloalkyl, or heterocyclyl. In some embodiments, R¹⁹ is hydrogen. Insome embodiments, R^(17a) is heteroaryl. In some embodiments, R^(17a) isheteroaryl and R¹⁹ is hydrogen. In some embodiments, R^(17a) is pyridyland R¹⁹ is hydrogen.

In an aspect, provided herein is a compound of Formula (3-A)

or a pharmaceutically acceptable salt thereof, wherein R¹⁹ is hydrogenor alkyl; Ria is nitro or alkoxy (e.g., —OCH₃); each of R², R⁴, R^(11a),or R^(11b) is independently hydrogen, alkyl, or alkoxy, or R^(11a) andR^(11b) are joined together to form oxo;

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent; and R⁵ is absent or hydrogen asdetermined by valency; provided that, when R², R^(11a), and R^(11b) arehydrogen, then R⁴ is alkyl, or when R⁴, R^(11a), and R^(11b) arehydrogen, then R² is alkyl, or when R⁴ is hydrogen, then R² is —OH oralkoxy, R^(11a) is hydrogen, and R^(11b) is —OH or alkoxy, or R² is —OHor alkoxy and R^(11a) and R^(11b) are joined together to form oxo.

In some embodiments, R⁴ is hydrogen, R² is —OH or alkoxy, R^(11a) ishydrogen, and R^(11b) is —OH or alkoxy. In some embodiments, R⁴ ishydrogen, R² is —OH or alkoxy, and R^(11a) and R^(11b) are joinedtogether to form oxo. In some embodiments, R^(11a) is nitro. In someembodiments, R^(11a) is alkoxy. In some embodiments, R^(11a) is methoxyand R² is methyl.

Additionally provided herein are compounds shown in Table 1 below or apharmaceutically acceptable salt thereof.

TABLE 1 Exemplary compounds of the invention. Compound Structure Number

 1

 2

 3

 4

 5

 6

 7

 8

 9

 10

 11

 12

 13

 14

 15

 16

 17

 18

 19

 20

 21

 22

 23

 24

 25

 26

 27

 28

 29

 30

 31

 32

 33

 34

 35

 36

 37

 38

 39

 40

 41

 42

 43

 44

 48

 49

 50

 55

 56

 57

 58

 60

 61

 63

 64

 65

 66

 69

 70

 73

 74

 75

 76

 77

 78

 79

 80

 83

 84

 85

 86

 87

 88

 89

 90

 91

 92

 93

 94

 95

 96

 97

 98

 99

100

101

102

103

104

105

106

107

108

109

110

111

112

118

119

120

121

122

123

125

125

126

ALTERNATIVE EMBODIMENTS

In an alterative embodiment, compounds described herein may alsocomprise one or more isotopic substitutions other than the substitutionof ¹H with deuterium. For example, hydrogen may also be 3H (T ortritium); carbon may be, for example, ¹³C or ¹⁴C; oxygen may be, forexample, ¹⁸O; nitrogen may be, for example, ¹⁵N, and the like. In otherembodiments, a particular isoptope (e.g., ³H, ¹³C, ¹⁴C, ¹⁸O or ¹⁵N) canrepresent at least 1%, at least 5%, at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95%, atleast 99%, or at least 99.9% of the total isotopic abundance of anelement that occupies a specific site of the compound.

Pharmaceutical Compositions

In one aspect, the invention provides a pharmaceutical compositioncomprising a compound of the present invention (also referred to as the“active ingredient”) and a pharmaceutically acceptable excipient. Incertain embodiments, the pharmaceutical composition comprises aneffective amount of the active ingredient. In certain embodiments, thepharmaceutical composition comprises a therapeutically effective amountof the active ingredient. In certain embodiments, the pharmaceuticalcomposition comprises a prophylactically effective amount of the activeingredient.

The pharmaceutical compositions provided herein can be administered by avariety of routes including, but not limited to, oral (enteral)administration, parenteral (by injection) administration, rectaladministration, transdermal administration, intradermal administration,intrathecal administration, subcutaneous (SC) administration,intravenous (IV) administration, intramuscular (IM) administration, andintranasal administration.

Generally, the compounds provided herein are administered in aneffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

When used to prevent the onset of a CNS-disorder, the compounds providedherein will be administered to a subject at risk for developing thecondition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Subjects at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

The pharmaceutical compositions provided herein can also be administeredchronically (“chronic administration”). Chronic administration refers toadministration of a compound or pharmaceutical composition thereof overan extended period of time, e.g., for example, over 3 months, 6 months,1 year, 2 years, 3 years, 5 years, etc, or may be continuedindefinitely, for example, for the rest of the subject's life. Incertain embodiments, the chronic administration is intended to provide aconstant level of the compound in the blood, e.g., within thetherapeutic window over the extended period of time.

The pharmaceutical compositions of the present invention may be furtherdelivered using a variety of dosing methods. For example, in certainembodiments, the pharmaceutical composition may be given as a bolus,e.g., in order to raise the concentration of the compound in the bloodto an effective level. The placement of the bolus dose depends on thesystemic levels of the active ingredient desired throughout the body,e.g., an intramuscular or subcutaneous bolus dose allows a slow releaseof the active ingredient, while a bolus delivered directly to the veins(e.g., through an IV drip) allows a much faster delivery which quicklyraises the concentration of the active ingredient in the blood to aneffective level. In other embodiments, the pharmaceutical compositionmay be administered as a continuous infusion, e.g., by IV drip, toprovide maintenance of a steady-state concentration of the activeingredient in the subject's body. Furthermore, in still yet otherembodiments, the pharmaceutical composition may be administered as firstas a bolus dose, followed by continuous infusion.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the compound is usually aminor component (from about 0.1 to about 50% by weight or preferablyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or excipients and processing aids helpful for forming thedesired dosing form.

With oral dosing, one to five and especially two to four and typicallythree oral doses per day are representative regimens. Using these dosingpatterns, each dose provides from about 0.01 to about 20 mg/kg of thecompound provided herein, with preferred doses each providing from about0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses, generally in anamount ranging from about 0.01 to about 20% by weight, preferably fromabout 0.1 to about 20% by weight, preferably from about 0.1 to about 10%by weight, and more preferably from about 0.5 to about 15% by weight.

Injection dose levels range from about 0.1 mg/kg/hour to at least 20mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 5 g/dayfor a 40 to 80 kg human patient.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable excipients knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable excipient and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s). When formulated as anointment, the active ingredients will typically be combined with eithera paraffinic or a water-miscible ointment base. Alternatively, theactive ingredients may be formulated in a cream with, for example anoil-in-water cream base. Such transdermal formulations are well-known inthe art and generally include additional ingredients to enhance thedermal penetration of stability of the active ingredients orFormulation. All such known transdermal formulations and ingredients areincluded within the scope provided herein.

The compounds provided herein can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The compounds of the present invention can also be administered insustained release forms or from sustained release drug delivery systems.A description of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The present invention also relates to the pharmaceutically acceptableacid addition salt of a compound of the present invention. The acidwhich may be used to prepare the pharmaceutically acceptable salt isthat which forms a non-toxic acid addition salt, i.e., a salt containingpharmacologically acceptable anions such as the hydrochloride,hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate,acetate, lactate, citrate, tartrate, succinate, maleate, fumarate,benzoate, para-toluenesulfonate, and the like.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of the present invention and a pharmaceuticallyacceptable excipient, e.g., a composition suitable for injection, suchas for intravenous (IV) administration.

Pharmaceutically acceptable excipients include any and all diluents orother liquid vehicles, dispersion or suspension aids, surface activeagents, isotonic agents, preservatives, lubricants and the like, assuited to the particular dosage form desired, e.g., injection. Generalconsiderations in the formulation and/or manufacture of pharmaceuticalcompositions agents can be found, for example, in Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980), and Remington: The Science andPractice of Pharmacy, 21^(st) Edition (Lippincott Williams & Wilkins,2005).

For example, injectable preparations, such as sterile injectable aqueoussuspensions, can be formulated according to the known art using suitabledispersing or wetting agents and suspending agents. Exemplary excipientsthat can be employed include, but are not limited to, water, sterilesaline or phosphate-buffered saline, or Ringer's solution.

In certain embodiments, the pharmaceutical composition further comprisesa cyclodextrin derivative. The most common cyclodextrins are α-, β- andγ-cyclodextrins consisting of 6, 7 and 8 □-1,4-linked glucose units,respectively, optionally comprising one or more substituents on thelinked sugar moieties, which include, but are not limited to,substituted or unsubstituted methylated, hydroxyalkylated, acylated, andsulfoalkylether substitution. In certain embodiments, the cyclodextrinis a sulfoalkyl ether β-cyclodextrin, e.g., for example, sulfobutylether β-cyclodextrin, also known as Captisol®. See, e.g., U.S. Pat. No.5,376,645. In certain embodiments, the composition compriseshexapropyl-D-cyclodextrin. In a more particular embodiment, thecomposition comprises hexapropyl-Q-cyclodextrin (10-50% in water).

The injectable composition can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

Generally, the compounds provided herein are administered in aneffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,response of the individual patient, the severity of the patient'ssymptoms, and the like.

The compositions are presented in unit dosage forms to facilitateaccurate dosing. The term “unit dosage forms” refers to physicallydiscrete units suitable as unitary dosages for human subjects and othermammals, each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include pre-filled, pre-measured ampules or syringes of theliquid compositions. In such compositions, the compound is usually aminor component (from about 0.1% to about 50% by weight or preferablyfrom about 1% to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form.

The compounds provided herein can be administered as the sole activeagent, or they can be administered in combination with other activeagents. In one aspect, the present invention provides a combination of acompound of the present invention and another pharmacologically activeagent. Administration in combination can proceed by any techniqueapparent to those of skill in the art including, for example, separate,sequential, concurrent, and alternating administration.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.General considerations in the formulation and/or manufacture ofpharmaceutical compositions can be found, for example, in Remington: TheScience and Practice of Pharmacy 21st ed., Lippincott Williams &Wilkins, 2005.

Methods of Use and Treatment

In an aspect, provided is a method of alleviating or preventing seizureactivity in a subject, comprising administering to the subject in needof such treatment an effective amount of a compound of the presentinvention. In some embodiments, the method alleviates or preventsepileptogenesis.

In some embodiments, such compounds are envisioned to be useful astherapeutic agents for treating a CNS-related disorder (e.g., sleepdisorder, a mood disorder such as depression, a schizophrenia spectrumdisorder, a convulsive disorder, epileptogenesis, a disorder of memoryand/or cognition, a movement disorder, a personality disorder, autismspectrum disorder, pain, traumatic brain injury, a vascular disease, asubstance abuse disorder and/or withdrawal syndrome, or tinnitus) in asubject in need (e.g., a subject with Rett syndrome, Fragile X syndrome,or Angelman syndrome). Exemplary CNS conditions related toGABA-modulation include, but are not limited to, sleep disorders [e.g.,insomnia], mood disorders [e.g., depression, dysthymic disorder (e.g.,mild depression), bipolar disorder (e.g., I and/or II), anxietydisorders (e.g., generalized anxiety disorder (GAD), social anxietydisorder), stress, post-traumatic stress disorder (PTSD), compulsivedisorders (e.g., obsessive compulsive disorder (OCD))], schizophreniaspectrum disorders [e.g., schizophrenia, schizoaffective disorder],convulsive disorders [e.g., epilepsy (e.g., status epilepticus (SE)),seizures], disorders of memory and/or cognition [e.g., attentiondisorders (e.g., attention deficit hyperactivity disorder (ADHD)),dementia (e.g., Alzheimer's type dementia, Lewis body type dementia,vascular type dementia], movement disorders [e.g., Huntington's disease,Parkinson's disease], personality disorders [e.g., anti-socialpersonality disorder, obsessive compulsive personality disorder], autismspectrum disorders (ASD) [e.g., autism, monogenetic causes of autismsuch as synaptophathy's, e.g., Rett syndrome, Fragile X syndrome,Angelman syndrome], pain [e.g., neuropathic pain, injury related painsyndromes, acute pain, chronic pain], traumatic brain injury (TBI),vascular diseases [e.g., stroke, ischemia, vascular malformations],substance abuse disorders and/or withdrawal syndromes [e.g., addition toopiates, cocaine, and/or alcohol], and tinnitus.

In yet another aspect, provided is a combination of a compound of thepresent invention and another pharmacologically active agent. Thecompounds provided herein can be administered as the sole active agentor they can be administered in combination with other agents.Administration in combination can proceed by any technique apparent tothose of skill in the art including, for example, separate, sequential,concurrent and alternating administration.

In another aspect, provided is a method of treating or preventing brainexcitability in a subject susceptible to or afflicted with a conditionassociated with brain excitability, comprising administering to thesubject an effective amount of a compound of the present invention tothe subject.

In yet another aspect, provided is a method of treating or preventingstress or anxiety in a subject, comprising administering to the subjectin need of such treatment an effective amount of a compound of thepresent invention, or a composition thereof.

In yet another aspect, provided is a method of alleviating or preventinginsomnia in a subject, comprising administering to the subject in needof such treatment an effective amount of a compound of the presentinvention, or a composition thereof.

In yet another aspect, provided is a method of inducing sleep andmaintaining substantially the level of REM sleep that is found in normalsleep, wherein substantial rebound insomnia is not induced, comprisingadministering an effective amount of a compound of the presentinvention.

In yet another aspect, provided is a method of alleviating or preventingPMS or PND in a subject, comprising administering to the subject in needof such treatment an effective amount of a compound of the presentinvention.

In yet another aspect, provided is a method of treating or preventingmood disorders in a subject, comprising administering to the subject inneed of such treatment an effective amount of a compound of the presentinvention. In certain embodiments the mood disorder is depression.

In yet another aspect, provided is a method of cognition enhancement ortreating memory disorder by administering to the subject atherapeutically effective amount of a compound of the present invention.In certain embodiments, the disorder is Alzheimer's disease. In certainembodiments, the disorder is Rett syndrome.

In yet another aspect, provided is a method of treating attentiondisorders by administering to the subject a therapeutically effectiveamount of a compound of the present invention. In certain embodiments,the attention disorder is ADHD.

In certain embodiments, the compound is administered to the subjectchronically. In certain embodiments, the compound is administered to thesubject orally, subcutaneously, intramuscularly, or intravenously.

Neuroendocrine Disorders and Dysfunction

Provided herein are methods that can be used for treating neuroendocrinedisorders and dysfunction. As used herein, “neuroendocrine disorder” or“neuroendocrine dysfunction” refers to a variety of conditions caused byimbalances in the body's hormone production directly related to thebrain. Neuroendocrine disorders involve interactions between the nervoussystem and the endocrine system. Because the hypothalamus and thepituitary gland are two areas of the brain that regulate the productionof hormones, damage to the hypothalamus or pituitary gland, e.g., bytraumatic brain injury, may impact the production of hormones and otherneuroendocrine functions of the brain. In some embodiments, theneuroendocrine disorder or dysfunction is associated with a women'shealth disorder or condition (e.g., a women's health disorder orcondition described herein). In some embodiments, the neuroendocrinedisorder or dysfunction is associated with a women's health disorder orcondition is polycystic ovary syndrome.

Symptoms of neuroendocrine disorder include, but are not limited to,behavioral, emotional, and sleep-related symptoms, symptoms related toreproductive function, and somatic symptoms; including but not limitedto fatigue, poor memory, anxiety, depression, weight gain or loss,emotional lability, lack of concentration, attention difficulties, lossof lipido, infertility, amenorrhea, loss of muscle mass, increased bellybody fat, low blood pressure, reduced heart rate, hair loss, anemia,constipation, cold intolerance, and dry skin.

Neurodegenerative Diseases and Disorders

The methods described herein can be used for treating neurodegenerativediseases and disorders. The term “neurodegenerative disease” includesdiseases and disorders that are associated with the progressive loss ofstructure or function of neurons, or death of neurons. Neurodegenerativediseases and disorders include, but are not limited to, Alzheimer'sdisease (including the associated symptoms of mild, moderate, or severecognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic andischemic injuries; ataxia and convulsion (including for the treatmentand prevention and prevention of seizures that are caused byschizoaffective disorder or by drugs used to treat schizophrenia);benign forgetfulness; brain edema; cerebellar ataxia including McLeodneuroacanthocytosis syndrome (MLS); closed head injury; coma; contusiveinjuries (e.g., spinal cord injury and head injury); dementias includingmulti-infarct dementia and senile dementia; disturbances ofconsciousness; Down syndrome; drug-induced or medication-inducedParkinsonism (such as neuroleptic-induced acute akathisia, acutedystonia, Parkinsonism, or tardive dyskinesia, neuroleptic malignantsyndrome, or medication-induced postural tremor); epilepsy; fragile Xsyndrome; Gilles de la Tourette's syndrome; head trauma; hearingimpairment and loss; Huntington's disease; Lennox syndrome;levodopa-induced dyskinesia; mental retardation; movement disordersincluding akinesias and akinetic (rigid) syndromes (including basalganglia calcification, corticobasal degeneration, multiple systematrophy, Parkinsonism-ALS dementia complex, Parkinson's disease,postencephalitic parkinsonism, and progressively supranuclear palsy);muscular spasms and disorders associated with muscular spasticity orweakness including chorea (such as benign hereditary chorea,drug-induced chorea, hemiballism, Huntington's disease,neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea),dyskinesia (including tics such as complex tics, simple tics, andsymptomatic tics), myoclonus (including generalized myoclonus and focalcyloclonus), tremor (such as rest tremor, postural tremor, and intentiontremor) and dystonia (including axial dystonia, dystonic writer's cramp,hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such asblepharospasm, oromandibular dystonia, and spasmodic dysphonia andtorticollis); neuronal damage including ocular damage, retinopathy ormacular degeneration of the eye; neurotoxic injury which followscerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebralischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia,perinatal asphyxia and cardiac arrest; Parkinson's disease; seizure;status epilecticus; stroke; tinnitus; tubular sclerosis, and viralinfection induced neurodegeneration (e.g., caused by acquiredimmunodeficiency syndrome (AIDS) and encephalopathies).Neurodegenerative diseases also include, but are not limited to,neurotoxic injury which follows cerebral stroke, thromboembolic stroke,hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia,amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methodsof treating or preventing a neurodegenerative disease also includetreating or preventing loss of neuronal function characteristic ofneurodegenerative disorder.

Mood Disorders

Also provided herein are methods for treating a mood disorder, forexample clinical depression, postnatal depression or postpartumdepression, perinatal depression, atypical depression, melancholicdepression, psychotic major depression, cataonic depression, seasonalaffective disorder, dysthymia, double depression, depressive personalitydisorder, recurrent brief depression, minor depressive disorder, bipolardisorder or manic depressive disorder, depression caused by chronicmedical conditions, treatment-resistant depression, refractorydepression, suicidality, suicidal ideation, or suicidal behavior. Insome embodiments, the method described herein provides therapeuticeffect to a subject suffering from depression (e.g., moderate or severedepression). In some embodiments, the mood disorder is associated with adisease or disorder described herein (e.g., neuroendocrine diseases anddisorders, neurodegenerative diseases and disorders (e.g., epilepsy),movement disorders, tremor (e.g., Parkinson's Disease), women's healthdisorders or conditions).

Clinical depression is also known as major depression, major depressivedisorder (MDD), severe depression, unipolar depression, unipolardisorder, and recurrent depression, and refers to a mental disordercharacterized by pervasive and persistent low mood that is accompaniedby low self-esteem and loss of interest or pleasure in normallyenjoyable activities. Some people with clinical depression have troublesleeping, lose weight, and generally feel agitated and irritable.Clinical depression affects how an individual feels, thinks, and behavesand may lead to a variety of emotional and physical problems.Individuals with clinical depression may have trouble doing day-to-dayactivities and make an individual feel as if life is not worth living.

Peripartum depression refers to depression in pregnancy. Symptomsinclude irritability, crying, feeling restless, trouble sleeping,extreme exhaustion (emotional and/or physical), changes in appetite,difficulty focusing, increased anxiety and/or worry, disconnectedfeeling from baby and/or fetus, and losing interest in formerlypleasurable activities.

Postnatal depression (PND) is also referred to as postpartum depression(PPD), and refers to a type of clinical depression that affects womenafter childbirth. Symptoms can include sadness, fatigue, changes insleeping and eating habits, reduced sexual desire, crying episodes,anxiety, and irritability. In some embodiments, the PND is atreatment-resistant depression (e.g., a treatment-resistant depressionas described herein). In some embodiments, the PND is refractorydepression (e.g., a refractory depression as described herein).

In some embodiments, a subject having PND also experienced depression,or a symptom of depression during preganancy. This depression isreferred to herein as) perinatal depression. In an embodiment, a subjectexperiencing perinatal depression is at increased risk of experiencingPND.

Atypical depression (AD) is characterized by mood reactivity (e.g.,paradoxical anhedonia) and positivity, significant weight gain orincreased appetite. Patients suffering from AD also may have excessivesleep or somnolence (hypersomnia), a sensation of limb heaviness, andsignificant social impairment as a consequence of hypersensitivity toperceived interpersonal rejection.

Melancholic depression is characterized by loss of pleasure (anhedonia)in most or all activities, failures to react to pleasurable stimuli,depressed mood more pronounced than that of grief or loss, excessiveweight loss, or excessive guilt.

Psychotic major depression (PMD) or psychotic depression refers to amajor depressive episode, in particular of melancholic nature, where theindividual experiences psychotic symptoms such as delusions andhallucinations.

Catatonic depression refers to major depression involving disturbancesof motor behavior and other symptoms. An individual may become mute andstuporose, and either is immobile or exhibits purposeless or bizarremovements.

Seasonal affective disorder (SAD) refers to a type of seasonaldepression wherein an individual has seasonal patterns of depressiveepisodes coming on in the fall or winter.

Dysthymia refers to a condition related to unipolar depression, wherethe same physical and cognitive problems are evident. They are not assevere and tend to last longer (e.g., at least 2 years).

Double depression refers to fairly depressed mood (dysthymia) that lastsfor at least 2 years and is punctuated by periods of major depression.

Depressive Personality Disorder (DPD) refers to a personality disorderwith depressive features.

Recurrent Brief Depression (RBD) refers to a condition in whichindividuals have depressive episodes about once per month, each episodelasting 2 weeks or less and typically less than 2-3 days.

Minor depressive disorder or minor depression refers to a depression inwhich at least 2 symptoms are present for 2 weeks.

Bipolar disorder or manic depressive disorder causes extreme mood swingsthat include emotional highs (mania or hypomania) and lows (depression).During periods of mania the individual may feel or act abnormally happy,energetic, or irritable. They often make poorly thought out decisionswith little regard to the consequnces. The need for sleep is usuallyreduced. During periods of depression there may be crying, poor eyecontact with others, and a negative outlook on life. The risk of suicideamong those with the disorder is high at greater than 6% over 20 years,while self harm occurs in 30-40%. Other mental health issues such asanxiety disorder and substance use disorder are commonly associated withbipolar disorder.

Depression caused by chronic medical conditions refers to depressioncaused by chronic medical conditions such as cancer or chronic pain,chemotherapy, chronic stress.

Treatment-resistant depression refers to a condition where theindividuals have been treated for depression, but the symptoms do notimprove. For example, antidepressants or psychological counseling(psychotherapy) do not ease depression symptoms for individuals withtreatment-resistant depression. In some cases, individuals withtreatment-resistant depression improve symptoms, but come back.Refractory depression occurs in patients suffering from depression whoare resistant to standard pharmacological treatments, includingtricyclic antidepressants, MAOIs, SSRIs, and double and triple uptakeinhibitors and/or anxiolytic drugs, as well as non-pharmacologicaltreatments (e.g., psychotherapy, electroconvulsive therapy, vagus nervestimulation and/or transcranial magnetic stimulation).

Post-surgical depression refers to feelings of depression that follow asurgical procedure (e.g., as a result of having to confront one'smortality). For example, individuals may feel sadness or empty moodpersistently, a loss of pleasure or interest in hobbies and activitiesnormally enjoyed, or a persistent felling of worthlessness orhopelessness.

Mood disorder associated with conditions or disorders of women's healthrefers to mood disorders (e.g., depression) associated with (e.g.,resulting from) a condition or disorder of women's health (e.g., asdescribed herein).

Suicidality, suicidal ideation, suicidal behavior refers to the tendencyof an individual to commit suicide. Suicidal ideation concerns thoughtsabout or an unusual preoccupation with suicide. The range of suicidalideation varies greatly, from e.g., fleeting thoughts to extensivethoughts, detailed planning, role playing, incomplete attempts. Symptomsinclude talking about suicide, getting the means to commit suicide,withdrawing from social contact, being preoccupied with death, feelingtrapped or hopeless about a situation, increasing use of alcohol ordrugs, doing risky or self-destructive things, saying goodbye to peopleas if they won't be seen again.

Symptoms of depression include persistent anxious or sad feelings,feelings of helplessness, hopelessness, pessimism, worthlessness, lowenergy, restlessness, difficulty sleeping, sleeplessness, irritability,fatigue, motor challenges, loss of interest in pleasurable activities orhobbies, loss of concentration, loss of energy, poor self-esteem,absence of positive thoughts or plans, excessive sleeping, overeating,appetite loss, insomnia, self-harm, thoughts of suicide, and suicideattempts. The presence, severity, frequency, and duration of symptomsmay vary on a case to case basis. Symptoms of depression, and relief ofthe same, may be ascertained by a physician or psychologist (e.g., by amental state examination).

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Hamilton Depression Score (HAM-D)) within 4, 3,2, 1 days; 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less. Insome embodiments, the therapeutic effect is a decrease from baseline inHAM-D score at the end of a treatment period (e.g., 12, 24, 48 hoursafter administration; 24, 48, 72, 96 hours or more). In someembodiments, the decrease from baseline in HAM-D score is from severe(e.g., HAM-D score of 24 or greater) to symptom-free (e.g., HAM-D scoreof 7 or lower). In some embodiments, the baseline score is about 10 to52 (e.g., more than 10, 15, or 20; 10 to 52, 12 to 52, 15 to 52, 17 to52, to 52, 22 to 52). In some embodiments, the baseline score is atleast 10, 15, or 20. In some embodiments, the HAM-D score at the end ofthe treatment period is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to6, 0 to 4, 0 to 3, 0 to 2, 1.8). In some embodiments, the HAM-D score atthe end of the treatment period is less than 10, 7, 5, or 3. In someembodiments, the decrease in HAM-D score is from a baseline score ofabout 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27)to a HAM-D score at the end of the treatment period is about 0 to 10(e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, 1.8). Insome embodiments, the decrease in the baseline HAM-D score to HAM-Dscore at the end of the treatment period is at least 1, 2, 3, 4, 5, 7,10, 25, 40, 50, or 100 fold). In some embodiments, the percentagedecrease in the baseline HAM-D score to HAM-D score at the end of thetreatment period is at least 50% (e.g., 60%, 70%, 80%, 90%). In someembodiments, the therapeutic effect is a decrease from baseline in HAM-Dscore at the end of a treatment period (e.g., 12, 24, 48 hours afteradministration; 24, 48, 72, 96 hours or more) at least 10, 15, or 20points. In some embodiments, the therapeutic effect is a decrease frombaseline in HAM-D score at the end of a treatment period (e.g., 12, 24,48 hours after administration; 24, 48, 72, 96 hours or more) at least 5,7, or 10 points more relative to the therapeutic effect provided by aplacebo treatment.

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Montgomery-Asberg Depression Rating Scale(MADRS)) within 4, 3, 2, 1 days; 96, 84, 72, 60, 48, 24, 20, 16, 12, 10,8 hours or less. The Montgomery-Asberg Depression Rating Scale (MADRS)is a ten-item diagnostic questionnaire (regarding apparent sadness,reported sadness, inner tension, reduced sleep, reduced appetite,concentration difficulties, lassitude, inability to feel, pessimisticthoughts, and suicidal thoughts) which psychiatrists use to measure theseverity of depressive episodes in patients with mood disorders. 0-6indicates normal/symptom absent; 7-19 indicates mild depression; 20-34indicates moderate depression; and >34 indicates severe depression. Insome embodiments, the therapeutic effect is a decrease from baseline inMADRS score at the end of a treatment period (e.g., 12, 24, 48 hoursafter administration; 24, 48, 60, 72, 96 hours or more). In someembodiments, the decrease from baseline in MADRS score is from severe(e.g., MADRS score of 30 or greater) to symptom-free (e.g., MADRS scoreof 20 or lower). For example, the mean change from baseline in MADRStotal score from treatment with a compound described herein is about−15, −20, −25, −30, while the mean change from baseline in MADRS totalscore from treatment with placebo is about −15, −10, −5.

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Edinburgh Postnatal Depression Scale (EPDS))within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less. In someembodiments, the therapeutic effect is a improvement measured by theEPDS.

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Clinical Global Impression-Improvement Scale(CGI)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less. Insome embodiments, the therapeutic effect is a CGI score of 2 or less.

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Generalized Anxiety Disorder 7-Item Scale(GAD-7)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less.

Anxiety Disorders

Provided herein are methods for treating anxiety disorders (e.g.,generalized anxiety disorder, panic disorder, obsessive compulsivedisorder, phobia, post-traumatic stress disorder). Anxiety disorder is ablanket term covering several different forms of abnormal andpathological fear and anxiety. Current psychiatric diagnostic criteriarecognize a wide variety of anxiety disorders.

Generalized anxiety disorder is a common chronic disorder characterizedby long-lasting anxiety that is not focused on any one object orsituation. Those suffering from generalized anxiety experiencenon-specific persistent fear and worry and become overly concerned witheveryday matters. Generalized anxiety disorder is the most commonanxiety disorder to affect older adults.

In panic disorder, a person suffers from brief attacks of intense terrorand apprehension, often marked by trembling, shaking, confusion,dizziness, nausea, difficulty breathing. These panic attacks, defined bythe APA as fear or discomfort that abruptly arises and peaks in lessthan ten minutes, can last for several hours and can be triggered bystress, fear, or even exercise; although the specific cause is notalways apparent. In addition to recurrent unexpected panic attacks, adiagnosis of panic disorder also requires that said attacks have chronicconsequences: either worry over the attacks' potential implications,persistent fear of future attacks, or significant changes in behaviorrelated to the attacks. Accordingly, those suffering from panic disorderexperience symptoms even outside of specific panic episodes. Often,normal changes in heartbeat are noticed by a panic sufferer, leadingthem to think something is wrong with their heart or they are about tohave another panic attack. In some cases, a heightened awareness(hypervigilance) of body functioning occurs during panic attacks,wherein any perceived physiological change is interpreted as a possiblelife threatening illness (i.e. extreme hypochondriasis).

Obsessive compulsive disorder is a type of anxiety disorder primarilycharacterized by repetitive obsessions (distressing, persistent, andintrusive thoughts or images) and compulsions (urges to perform specificacts or rituals). The OCD thought pattern may be likened tosuperstitions insofar as it involves a belief in a causativerelationship where, in reality, one does not exist. Often the process isentirely illogical; for example, the compulsion of walking in a certainpattern may be employed to alleviate the obsession of impending harm.And in many cases, the compulsion is entirely inexplicable, simply anurge to complete a ritual triggered by nervousness. In a minority ofcases, sufferers of OCD may only experience obsessions, with no overtcompulsions; a much smaller number of sufferers experience onlycompulsions.

The single largest category of anxiety disorders is that of phobia,which includes all cases in which fear and anxiety is triggered by aspecific stimulus or situation. Sufferers typically anticipateterrifying consequences from encountering the object of their fear,which can be anything from an animal to a location to a bodily fluid.

Post-traumatic stress disorder or PTSD is an anxiety disorder whichresults from a traumatic experience. Post-traumatic stress can resultfrom an extreme situation, such as combat, rape, hostage situations, oreven serious accident. It can also result from long term (chronic)exposure to a severe stressor, for example soldiers who endureindividual battles but cannot cope with continuous combat. Commonsymptoms include flashbacks, avoidant behaviors, and depression.

Women's Health Disorders

Provided herein are methods for treating conditions or disorders relatedto women's health. Conditions or disorders related to women's healthinclude, but are not limited to, Gynecological health and disorders(e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder(PMDD)), pregnancy issues (e.g., miscarriage, abortion), infertility andrelated disorders (e.g., polycystic ovary syndrome (PCOS)), otherdisorders and conditions, and issues related to women's overall healthand wellness (e.g., menopause).

Gynecological health and disorders affecting women include menstruationand menstrual irregularities; urinary tract health, including urinaryincontinence and pelvic floor disorders; and such disorders as bacterialvaginosis, vaginitis, uterine fibroids, and vulvodynia.

Premenstrual syndrome (PMS) refers to physical and emotional symptomsthat occur in the one to two weeks before a women's period. Symptomsvary but can include bleeding, mood swings, tender breasts, foodcravings, fatigue, irritability, acne, and depression.

Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. Thesymptoms of PMDD are similar to PMS but more severe and may interferewith work, social activity, and relationships. PMDD symptoms includemood swings, depressed mood or feelings of hopelessness, marked anger,increased interpersonal conflicts, tension and anxiety, irritability,decreased interest in usual activites, difficulty concentrating,fatigue, change in appetite, feeling out of control or overwhelmed,sleep problems, physical problems (e.g., bloating, breast tenderness,swelling, headaches, joint or muscle pain).

Pregnancy issues include preconception care and prenatal care, pregnancyloss (miscarriage and stillbirth), preterm labor and premature birth,sudden infant death syndrome (SIDS), breastfeeding, and birth defects.

Miscarriage refers to a pregnancy that ends on its own, within the first20 weeks of gestation.

Abortion refers to the deliberate termination of a pregnancy, which canbe performed during the first 28 weeks of pregnancy.

Infertility and related disorders include uterine fibroids, polycysticovary syndrome, endometriosis, and primary ovarian insufficiency.

Polycystic ovary syndrome (PCOS) refers to an endocrine system disorderamong women of reproductive age. PCOS is a set of symptoms resultingfrom an elevated male hormone in women. Most women with PCOS grow manysmall cysts on their ovaries. Symptoms of PCOS include irregular or nomenstrual periods, heavy periods, excess body and facial hair, acne,pelvic pain, difficulty getting pregnant, and patches of thick, darker,velvety skin. PCOS may be associated with conditions including type 2diabetes, obesity, obstructive sleep apnea, heart disease, mooddisorders, and endometrial cancer.

Other disorders and conditions that affect only women include Turnersyndrome, Rett syndrome, and ovarian and cervical cancers.

Issues related to women's overall health and wellness include violenceagainst women, women with disabilities and their unique challenges,osteoporosis and bone health, and menopause.

Menopause refers to the 12 months after a woman's last menstrual periodand marks the end of menstrual cycles. Menopause typically occurs in awoman's 40s or 50s. Physical symptoms such as hot flashes and emotionalsymptoms of menopause may disrupt sleep, lower energy, or triggeranxiety or feelings of sadness or loss. Menopause includes nautralmenopause and surgical menopause, which is a type of induced menopausedue to an event such as surgery (e.g., hysterectomy, oophorectomy;cancer). It is induced when the ovaries are gravely damaged by, e.g.,radiation, chemotherapy, or other medications.

Epilepsy

The compounds described herein, or a pharmaceutically acceptable salt,or a pharmaceutically acceptable composition thereof, can be used in amethod described herein, for example in the treatment of a disorderdescribed herein such as epilepsy, status epilepticus, or seizure, forexample as described in WO2013/112605 and WO/2014/031792, the contentsof which are incorporated herein in their entirety.

Epilepsy is a brain disorder characterized by repeated seizures overtime. Types of epilepsy can include, but are not limited to generalizedepilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy,epilepsy with grand-mal seizures on awakening, West syndrome,Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy,frontal lobe epilepsy, benign focal epilepsy of childhood.

Epileptogenesis

The compounds and methods described herein can be used to treat orprevent epileptogenesis. Epileptogenesis is a gradual process by which anormal brain develops epilepsy (a chronic condition in which seizuresoccur). Epileptogenesis results from neuronal damage precipitated by theinitial insult (e.g., status epilepticus).

Status Epilepticus (SE)

Status epilepticus (SE) can include, e.g., convulsive statusepilepticus, e.g., early status epilepticus, established statusepilepticus, refractory status epilepticus, super-refractory statusepilepticus; non-convulsive status epilepticus, e.g., generalized statusepilepticus, complex partial status epilepticus; generalized periodicepileptiform discharges; and periodic lateralized epileptiformdischarges. Convulsive status epilepticus is characterized by thepresence of convulsive status epileptic seizures, and can include earlystatus epilepticus, established status epilepticus, refractory statusepilepticus, super-refractory status epilepticus. Early statusepilepticus is treated with a first line therapy. Established statusepilepticus is characterized by status epileptic seizures which persistdespite treatment with a first line therapy, and a second line therapyis administered. Refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline and a second line therapy, and a general anesthetic is generallyadministered. Super refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline therapy, a second line therapy, and a general anesthetic for 24hours or more.

Non-convulsive status epilepticus can include, e.g., focalnon-convulsive status epilepticus, e.g., complex partial non-convulsivestatus epilepticus, simple partial non-convulsive status epilepticus,subtle non-convulsive status epilepticus; generalized non-convulsivestatus epilepticus, e.g., late onset absence non-convulsive statusepilepticus, atypical absence non-convulsive status epilepticus, ortypical absence non-convulsive status epilepticus.

The compound described herein, or pharmaceutically acceptable salt, or apharmaceutically acceptable composition thereof, can also beadministered as a prophylactic to a subject having a CNS disorder e.g.,a traumatic brain injury, status epilepticus, e.g., convulsive statusepilepticus, e.g., early status epilepticus, established statusepilepticus, refractory status epilepticus, super-refractory statusepilepticus; non-convulsive status epilepticus, e.g., generalized statusepilepticus, complex partial status epilepticus; generalized periodicepileptiform discharges; and periodic lateralized epileptiformdischarges; prior to the onset of a seizure.

Seizure

A seizure is the physical findings or changes in behavior that occurafter an episode of abnormal electrical activity in the brain. The term“seizure” is often used interchangeably with “convulsion.” Convulsionsare when a person's body shakes rapidly and uncontrollably. Duringconvulsions, the person's muscles contract and relax repeatedly.

Based on the type of behavior and brain activity, seizures are dividedinto two broad categories: generalized and partial (also called local orfocal). Classifying the type of seizure helps doctors diagnose whetheror not a patient has epilepsy.

Generalized seizures are produced by electrical impulses from throughoutthe entire brain, whereas partial seizures are produced (at leastinitially) by electrical impulses in a relatively small part of thebrain. The part of the brain generating the seizures is sometimes calledthe focus.

There are six types of generalized seizures. The most common anddramatic, and therefore the most well known, is the generalizedconvulsion, also called the grand-mal seizure. In this type of seizure,the patient loses consciousness and usually collapses. The loss ofconsciousness is followed by generalized body stiffening (called the“tonic” phase of the seizure) for 30 to 60 seconds, then by violentjerking (the “clonic” phase) for 30 to 60 seconds, after which thepatient goes into a deep sleep (the “postictal” or after-seizure phase).During grand-mal seizures, injuries and accidents may occur, such astongue biting and urinary incontinence.

Absence seizures cause a short loss of consciousness (just a fewseconds) with few or no symptoms. The patient, most often a child,typically interrupts an activity and stares blankly. These seizuresbegin and end abruptly and may occur several times a day. Patients areusually not aware that they are having a seizure, except that they maybe aware of “losing time.” Myoclonic seizures consist of sporadic jerks,usually on both sides of the body. Patients sometimes describe the jerksas brief electrical shocks. When violent, these seizures may result indropping or involuntarily throwing objects.

Clonic seizures are repetitive, rhythmic jerks that involve both sidesof the body at the same time.

Tonic seizures are characterized by stiffening of the muscles.

Atonic seizures consist of a sudden and general loss of muscle tone,particularly in the arms and legs, which often results in a fall.

Seizures described herein can include epileptic seizures; acuterepetitive seizures; cluster seizures; continuous seizures; unremittingseizures; prolonged seizures; recurrent seizures; status epilepticusseizures, e.g., refractory convulsive status epilepticus, non-convulsivestatus epilepticus seizures; refractory seizures; myoclonic seizures;tonic seizures; tonic-clonic seizures; simple partial seizures; complexpartial seizures; secondarily generalized seizures; atypical absenceseizures; absence seizures; atonic seizures; benign Rolandic seizures;febrile seizures; emotional seizures; focal seizures; gelastic seizures;generalized onset seizures; infantile spasms; Jacksonian seizures;massive bilateral myoclonus seizures; multifocal seizures; neonatalonset seizures; nocturnal seizures; occipital lobe seizures; posttraumatic seizures; subtle seizures; Sylvan seizures; visual reflexseizures; or withdrawal seizures. In some embodiments, the seizure is ageneralized seizure associated with Dravet Syndrome, Lennox-GastautSyndrome, Tuberous Sclerosis Complex, Rett Syndrome or PCDH19 FemalePediatric Epilepsy.

Movement Disorders

Also described herein are methods for treating a movement disorder. Asused herein, “movement disorders” refers to a variety of diseases anddisorders that are associated with hyperkinetic movement disorders andrelated abnormalities in muscle control. Exemplary movement disordersinclude, but are not limited to, Parkinson's disease and parkinsonism(defined particularly by bradykinesia), dystonia, chorea andHuntington's disease, ataxia, tremor (e.g., essential tremor), myoclonusand startle, tics and Tourette syndrome, Restless legs syndrome, stiffperson syndrome, and gait disorders.

Tremor

The methods described herein can be used to treat tremor, can be used totreat cerebellar tremor or intention tremor, dystonic tremor, essentialtremor, orthostatic tremor, parkinsonian tremor, physiological tremor,psychogenic tremor, or rubral tremor. Tremor includes hereditary,degenerative, and idiopathic disorders such as Wilson's disease,Parkinson's disease, and essential tremor, respectively; metabolicdiseases (e.g., thyoid-parathyroid-, liver disease and hypoglycemia);peripheral neuropathies (associated with Charcot-Marie-Tooth,Roussy-Levy, diabetes mellitus, complex regional pain syndrome); toxins(nicotine, mercury, lead, CO, Manganese, arsenic, toluene); drug-induced(narcoleptics, tricyclics, lithium, cocaine, alcohol, adrenaline,bronchodilators, theophylline, caffeine, steroids, valproate,amiodarone, thyroid hormones, vincristine); and psychogenic disorders.Clinical tremor can be classified into physiologic tremor, enhancedphysiologic tremor, essential tremor syndromes (including classicalessential tremor, primary orthostatic tremor, and task- andposition-specific tremor), dystonic tremor, parkinsonian tremor,cerebellar tremor, Holmes' tremor (i.e., rubral tremor), palatal tremor,neuropathic tremor, toxic or drug-induced tremor, and psychogenictremor.

Tremor is an involuntary, at times rhythmic, muscle contraction andrelaxation that can involve oscillations or twitching of one or morebody parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk,legs).

Cerebellar tremor or intention tremor is a slow, broad tremor of theextremities that occurs after a purposeful movement. Cerebellar tremoris caused by lesions in or damage to the cerebellum resulting from,e.g., tumor, stroke, disease (e.g., multiple sclerosis, an inheriteddegenerative disorder).

Dystonic tremor occurs in individuals affected by dystonia, a movementdisorder in which sustained involuntary muscle contractions causetwisting and repetitive motions and/or painful and abnormal postures orpositions. Dystonic tremor may affect any muscle in the body. Dystonictremors occurs irregularly and often can be relieved by complete rest.

Essential tremor or benign essential tremor is the most common type oftremor. Essential tremor may be mild and nonprogressive in some, and maybe slowly progressive, starting on one side of the body but affect bothsides within 3 years. The hands are most often affected, but the head,voice, tongue, legs, and trunk may also be involved. Tremor frequencymay decrease as the person ages, but severity may increase. Heightenedemotion, stress, fever, physical exhaustion, or low blood sugar maytrigger tremors and/or increase their severity. Symptoms generallyevolve over time and can be both visible and persistent following onset.

Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz)rhythmic muscle contractions that occurs in the legs and trunkimmediately after standing. Cramps are felt in the thighs and legs andthe patient may shake uncontrollably when asked to stand in one spot.Orthostatic tremor may occurs in patients with essential tremor.

Parkinsonian tremor is caused by damage to structures within the brainthat control movement. Parkinsonian tremor is often a precursor toParkinson's disease and is typically seen as a “pill-rolling” action ofthe hands that may also affect the chin, lips, legs, and trunk. Onset ofparkinsonian tremor typically begins after age 60. Movement starts inone limb or on one side of the body and can progress to include theother side.

Physiological tremor can occur in normal individuals and have noclinical significance. It can be seen in all voluntary muscle groups.Physiological tremor can be caused by certain drugs, alcohol withdrawl,or medical conditions including an overactive thyroid and hypoglycemia.The tremor classically has a frequency of about 10 Hz.

Psychogenic tremor or hysterical tremor can occur at rest or duringpostural or kinetic movement. Patient with psychogenic tremor may have aconversion disorder or another psychiatric disease.

Rubral tremor is characterized by coarse slow tremor which can bepresent at rest, at posture, and with intention. The tremor isassociated with conditions that affect the red nucleus in the midbrain,classical unusual strokes.

Parkinson's Disease affects nerve cells in the brain that producedopamine. Symptoms include muscle rigidity, tremors, and changes inspeech and gait. Parkinsonism is characterized by tremor, bradykinesia,rigidity, and postural instability. Parkinsonism shares symptoms foundin Parkinson's Disease, but is a symptom complex rather than aprogressive neurodegenerative disease.

Dystonia is a movement disorder characterized by sustained orintermittent muscle contractions causing abnormal, often repetitivemovements or postures. Dystonic movements can be patterned, twisting,and may be tremulous. Dystonia is often initiated or worsened byvoluntary action and associated with overflow muscle activation.

Chorea is a neurological disorder characterized by jerky involuntarymovements typically affecting the shoulders, hips, and face.

Huntington's Disease is an inherited disease that causes nerve cells inthe brain to waste away.

Symptoms include uncontrolled movements, clumsiness, and balanceproblems. Huntington's disease can hinder walk, talk, and swallowing.

Ataxia refers to the loss of full control of bodily movements, and mayaffect the fingers, hands, arms, legs, body, speech, and eye movements.

Myloclonus and Startle is a response to a sudden and unexpectedstimulus, which can be acoustic, tactile, visual, or vestibular.

Tics are an involuntary movement usually onset suddenly, brief,repetitive, but non-rhythmical, typically imitating normal behavior andoften occurring out of a background of normal activity. Tics can beclassified as motor or vocal, motor tics associated with movements whilevocal tics associated with sound. Tics can be characterized as simple orcomplex. For example simple motor tics involve only a few musclesrestricted to a specific body part. Tourette Syndrome is an inheritedneuropsychiatric disorder with onset in childhood, characterized bymultiple motor tics and at least one vocal tic.

Restless Legs Syndrome is a neurologic sensorimotor disordercharacterized by an overwhelming urge to move the legs when at rest.

Stiff Person Syndrome is a progressive movement disorder characterizedby involuntary painful spasms and rigidity of muscles, usually involvingthe lower back and legs. Stiff-legged gait with exaggerated lumbarhyperlordosis typically results. Characteristic abnormality on EMGrecordings with continuous motor unit activity of the paraspinal axialmuscles is typically observed. Variants include “stiff-limb syndrome”producing focal stiffness typically affecting distal legs and feet.

Gait disorders refer to an abnormalitiy in the manner or style ofwalking, which results from neuromuscular, arthritic, or other bodychanges. Gait is classified according to the system responsible forabnormal locomotion, and include hemiplegic gait, diplegic gait,neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait,ataxic gait, and sensory gait.

Anesthesia/Sedation

Anesthesia is a pharmacologically induced and reversible state ofamnesia, analgesia, loss of responsiveness, loss of skeletal musclereflexes, decreased stress response, or all of these simultaneously.These effects can be obtained from a single drug which alone providesthe correct combination of effects, or occasionally with a combinationof drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achievevery specific combinations of results. Anesthesia allows patients toundergo surgery and other procedures without the distress and pain theywould otherwise experience.

Sedation is the reduction of irritability or agitation by administrationof a pharmacological agent, generally to facilitate a medical procedureor diagnostic procedure.

Sedation and analgesia include a continuum of states of consciousnessranging from minimal sedation (anxiolysis) to general anesthesia.

Minimal sedation is also known as anxiolysis. Minimal sedation is adrug-induced state during which the patient responds normally to verbalcommands. Cognitive function and coordination may be impaired.Ventilatory and cardiovascular functions are typically unaffected.

Moderate sedation/analgesia (conscious sedation) is a drug-induceddepression of consciousness during which the patient respondspurposefully to verbal command, either alone or accompanied by lighttactile stimulation. No interventions are usually necessary to maintaina patent airway. Spontaneous ventilation is typically adequate.Cardiovascular function is usually maintained.

Deep sedation/analgesia is a drug-induced depression of consciousnessduring which the patient cannot be easily aroused, but respondspurposefully (not a reflex withdrawal from a painful stimulus) followingrepeated or painful stimulation. Independent ventilatory function may beimpaired and the patient may require assistance to maintain a patentairway. Spontaneous ventilation may be inadequate. Cardiovascularfunction is usually maintained.

General anesthesia is a drug-induced loss of consciousness during whichthe patient is not arousable, even to painful stimuli. The ability tomaintain independent ventilatory function is often impaired andassistance is often required to maintain a patent airway. Positivepressure ventilation may be required due to depressed spontaneousventilation or drug-induced depression of neuromuscular function.Cardiovascular function may be impaired.

Sedation in the intensive care unit (ICU) allows the depression ofpatients' awareness of the environment and reduction of their responseto external stimulation. It can play a role in the care of thecritically ill patient, and encompasses a wide spectrum of symptomcontrol that will vary between patients, and among individualsthroughout the course of their illnesses. Heavy sedation in criticalcare has been used to facilitate endotracheal tube tolerance andventilator synchronization, often with neuromuscular blocking agents.

In some embodiments, sedation (e.g., long-term sedation, continuoussedation) is induced and maintained in the ICU for a prolonged period oftime (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 week, 3 weeks, 1month, 2 months). Long-term sedation agents may have long duration ofaction.

Sedation agents in the ICU may have short elimination half-life.

Procedural sedation and analgesia, also referred to as conscioussedation, is a technique of administering sedatives or dissociativeagents with or without analgesics to induce a state that allows asubject to tolerate unpleasant procedures while maintainingcardiorespiratory function.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic examplesdescribed in this application are offered to illustrate the inventionprovided herein and are not to be construed in any way as limiting itsscope.

Materials and Methods

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

The compounds provided herein may be isolated and purified by knownstandard procedures. Such procedures include (but are not limited to)recrystallization, column chromatography, HPLC, or supercritical fluidchromatography (SFC). The following schemes are presented with detailsas to the preparation of representative oxysterols that have been listedherein. The compounds provided herein may be prepared from known orcommercially available starting materials and reagents by one skilled inthe art of organic synthesis. Exemplary chiral columns available for usein the separation/purification of the enantiomers/diastereomers providedherein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB,CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF,CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

Exemplary general method for preparative HPLC: Column: Durashell. Mobilephase: A: water, B: acetonitrile. % B at 0 min: 41%, % B at 8 min: 71%,flow rate: 35 mL/min, detection wavelength: 220 nm.

Exemplary general method for analytical HPLC: Mobile phase: A: water (10mM NH₄HCO₃), B: acetonitrile Gradient: 5%-95% B in 1.6 or 2 min, flowrate: 1.8 or 2 mL/min; Column: XBridge C18, 4.6*50 mm, 3.5 μm at 45 C.

Exemplary general method for SFC: Column: CHIRALPAK® AD (250 mm*30 mm, 5μm), A=supercritical CO₂, B=MeOH (0.1% NH₃—H₂O), A:B=70:30, flow rate:60 mL/min, column temperature: 38° C., nozzle pressure: 100 bar,detection wavelength=220 nm.

Exemplary LCMS conditions include:

30-90AB_2MIN_E Column Xtimate C18 2.1*30 mm, 3 um Mobile Phase A:water(4 L) + TFA(1.5 mL) B: acetonitrile(4 L) + TFA(0.75 mL) TIME(min) B% 0 30 0.9 90 1.5 90 1.51 30 2 30 Flow Rate 1.2 mL/min wavelength UV 220nm Oven Temp 50° C. MS ionization ESI Detector PDA, ELSD 10-80AB_2MIN_EColumn Xtimate C18 2.1*30 mm, 3 um Mobile Phase A: water(4 L) + TFA(1.5mL) B: acetonitrile(4 L) + TFA(0.75 mL) TIME(min) B % 0 10 0.9 80 1.5 801.51 10 2 10 Flow Rate 1.2 mL/min wavelength UV 220 nm Oven Temp 50° C.MS ionization ESI Detector PDA, ELSD 30-90CD_3MIN_E Column Xbrige ShieldRP-18, 5 um, 2.1*50 mm Mobile Phase A: water(1 L) + NH3H2O(0.5 mL) B:acetonitrile TIME(min) B % 0 30 2 90 2.48 90 2.49 30 3 30 Flow Rate 1.0mL/min wavelength UV 220 nm Oven Temp 30° C. MS ionization ESI DetectorPDA, ELSD

Steroid Inhibition of TBPS Binding

[³⁵S]-t-Butylbicyclophosphorothionate (TBPS) binding assays using ratbrain cortical membranes in the presence of 5 mM GABA has been described(Gee et al, J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson etal, Mol. Pharmacol. 1994, 46, 977-985; Lewin, A. H et al., Mol.Pharmacol. 1989, 35, 189-194).

Briefly, cortices are rapidly removed following decapitation of carbondioxide-anesthetized Sprague-Dawley rats (200-250 μg). The cortices arehomogenized in 10 volumes of ice-cold 0.32 M sucrose using aglass/teflon homogenizer and centrifuged at 1500×g for 10 min at 4° C.The resultant supernatants are centrifuged at 10,000×g for 20 min at 4°C. to obtain the P2 pellets. The P2 pellets are resuspended in 200 mMNaCl/50 mM Na—K phosphate pH 7.4 buffer and centrifuged at 10,000×g for10 min at 4° C. This washing procedure is repeated twice and the pelletsare resuspended in 10 volumes of buffer. Aliquots (100 mL) of themembrane suspensions are incubated with 3 nM [³⁵S]-TBPS and 5 mLaliquots of test drug dissolved in dimethyl sulfoxide (DMSO) (final0.5%) in the presence of 5 mM GABA. The incubation is brought to a finalvolume of 1.0 mL with buffer. Nonspecific binding is determined in thepresence of 2 mM unlabeled TBPS and ranged from 15 to 25%. Following a90 min incubation at room temp, the assays are terminated by filtrationthrough glass fiber filters (Schleicher and Schuell No. 32) using a cellharvester (Brandel) and rinsed three times with ice-cold buffer. Filterbound radioactivity is measured by liquid scintillation spectrometry.Non-linear curve fitting of the overall data for each drug averaged foreach concentration is done using Prism (GraphPad). The data are fit to apartial instead of a full inhibition model if the sum of squares issignificantly lower by F-test. Similarly, the data are fit to a twocomponent instead of a one component inhibition model if the sum ofsquares is significantly lower by F-test. The concentration of testcompound producing 50% inhibition (IC₅₀) of specific binding and themaximal extent of inhibition (I_(max)) are determined for the individualexperiments with the same model used for the overall data and then themeans±SEM.s of the individual experiments are calculated. Picrotoxinserves as the positive control for these studies as it has beendemonstrated to robustly inhibit TBPS binding.

Various compounds are or can be screened to determine their potential asmodulators of [³⁵S]-TBPS binding in vitro. These assays are or can beperformed in accordance with the above discussed procedures. The resultsof the TBPS binding assays are shown in Table 2.

Abbreviations

PCC: pyridinium chlorochromate; t-BuOK: potassium tert-butoxide; 9-BBN:9-borabicyclo[3.3.1]nonane; Pd(t-Bu₃P)₂:bis(tri-tert-butylphosphine)palladium(0); AcCl: acetyl chloride;i-PrMgCl: Isopropylmagnesium chloride; TBSCl:tert-Butyl(chloro)dimethylsilane; (i-PrO)₄Ti: titaniumtetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me: methyl;i-Pr: iso-propyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl;BzCl: benzoyl chloride; CsF: cesium fluoride; DCC:dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP:4-dimethylaminopyridine; DMP: Dess-Martin periodinane; EtMgBr:ethylmagnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine; AlaOH:alanine; Boc: t-butoxycarbonyl. Py: pyridine; TBAF:tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TBS:t-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF₃:(Trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: butyl;Ti(OiPr)₄: tetraisopropoxytitanium; LAH: Lithium Aluminium Hydride; LDA:lithium diisopropylamide; LiOH.H₂O: lithium hydroxide hydrates; MAD:methyl aluminum bis(2,6-di-t-butyl-4-methylphenoxide); MeCN:acetonitrile; NBS: N-bromosuccinimide; Na₂SO₄: sodium sulfate; Na₂S₂O₃:sodium thiosulfate; PE: petroleum ether; MeCN: acetonitrile; MeOH:methanol; Boc: t-butoxycarbonyl; MTBE: methyl tert-butyl ether; EDCI:N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride; HATU:1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate.

Example 1. Synthesis of Compound 1

The synthesis of A1 is disclosed in WO2013/56181 A1.

Step 1 (A2). Liquid bromine (7.46 g, 46.7 mmol) was added slowly to avigorously stirred sodium hydroxide aqueous solution (62.3 mL, 3 M, 187mmol) at 0° C. When all the bromine dissolved, the mixture was dilutedwith cold dioxane (15 mL) and was added slowly to a stirring solution ofA1 (5 g, 15.6 mmol) in dioxane (20 mL) and water (15 mL). Thehomogeneous yellow solution became colorless slowly and a whiteprecipitate formed. The reaction mixture was stirred at 25° C. for 16hours. The remaining oxidizing reagent was quenched with aqueous Na₂S₂O₃(30 mL) and the mixture was then heated at 80° C. until the solidmaterial dissolved. Acidification of the solution with hydrochloric acid(3 N) furnished a white precipitate. The solid was collected byfiltration and washed with water (3×100 mL) to give a solid, which wasdried in vacuo to afford crude product. The crude product was trituratedwith toluene (40 mL) to give A2 (3.6 g, 72%) as a solid.

¹H NMR (CDCl₃, 400 MHz) δ 2.43-2.38 (m, 1H), 2.07-2.04 (m, 2H),1.82-1.79 (m, 4H), 1.57-1.60 (m, 3H), 1.57-1.40 (m, 7H), 1.39-1.30 (m,8H), 1.29-1.06 (m, 3H), 0.72 (s, 3H).

Step 2 (Compound 1) To a solution of A2 (100 mg, 0.312 mmol) in DCM (8mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at25° C. After stirring at 25° C. for 30 mins, phenylmethylamine (53.4 mg,0.499 mmol) was added. The mixture was stirred at 25° C. for 12 h. Water(8 mL) was added. The mixture was extracted with DCM (2×8 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated in vacuo to give a crude product, which was purified byprep. HPLC (Column: Xtimate C18 150*25 mm*5 um; Conditions: water (0.05%ammonia hydroxide v/v)-ACN; Gradient 50%-80% B; Gradient Time (min): 10)and lyophilized to give Compound 1 (77 mg, 61%) as a solid

¹H NMR (CDCl₃, 400 MHz) δ 7.40-7.26 (m, 5H), 5.54 (s, 1H), 4.55-4.35 (m,2H), 2.25-2.10 (m, 2H), 1.96-1.60 (m, 8H), 1.57-1.30 (m, 6H), 1.25-1.15(m, 8H), 1.15-1.00 (m, 4H), 0.71 (s, 3H).

LCMS Rt=1.797 min in 3 min chromatography, 30-90 CD, purity 100%, MS ESIcalcd. For C₂₇H₄₀NO₂+[M+H]⁺ 410, found 410.

Example 2. Synthesis of Compound 2

Step 1 (Compound 2). To a solution of A2 (100 mg, 0.312 mmol) in DCM (8mL) were added TEA (236 mg, 2.34 mmol) and HATU (266 mg, 0.702 mmol).After stirring for 10 min, diethylamine (54.7 mg, 0.749 mmol) was added.The mixture was stirred at 25° C. for 12 h. The reaction was treatedwith water (8 mL) and extracted with DCM (2×8 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄, concentrated in vacuoto give a crude product, which was purified by prep. HPLC (Column:Xtimate C18 150*25 mm*5 um; Conditions: water (0.05% ammonia hydroxidev/v)-ACN; Gradient 52%-82% B; Gradient Time (min): 10) and lyophilizedto give Compound 2 (100 mg, 57%) as a solid.

¹H NMR (CDCl₃, 400 MHz) δ 3.77-3.65 (m, 2H), 3.15-2.99 (m, 2H),2.65-2.55 (m, 1H), 2.30-2.20 (m, 1H), 1.90-1.55 (m, 8H), 1.50-1.30 (m,7H), 1.30-1.15 (m, 8H), 1.15-1.00 (m, 9H), 0.74 (s, 3H).

LCMS Rt=1.739 min in 3 min chromatography, 30-90 CD, purity 100%, MS ESIcalcd. For C₂₄H₄₂NO₂ ⁺ [M+H]⁺ 376, found 376.

Example 3. Synthesis of Compound 3

Step 1 (Compound 3). To a solution of A2 (200 mg, 0.62 mmol) in DCM (8mL) was added TEA (314 mg, 3.11 mmol) and HATU (355 mg, 0.936 mmol) at25° C. After stirring at 25° C. for 30 mins, aniline (92.9 mg, 0.998mmol) was added. The mixture was stirred at 25° C. for 16 h and treatedwith water (8 mL), extracted with DCM (2×8 mL). The organic layers werewashed with brine (2×10 mL), dried over Na₂SO₄, filtered, concentratedin vacuo to give a crude product, which was triturated with MeOH (12 mL)at 25° C. to give 90 mg of an impure product. The impure product wasre-crystallized from MeCN (20 mL) at 65° C. and filtered at 25° C. togive the product, which was dissolved in MeCN (30 mL) at 65° C. andconcentrated in vacuo to give Compound 3 (44 mg, 49%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J=7.8 Hz, 2H), 7.35-7.28 (m, 2H),7.12-7.05 (m, 1H), 6.95 (brs, 1H), 2.35-2.22 (m, 2H), 2.06-1.98 (m, 1H),1.89-1.60 (m, 7H), 1.52-1.23 (m, 15H), 1.20-1.04 (m, 3H), 0.75 (s, 3H).

LCMS Rt=0.932 min in 2 min chromatography, 5-95AB_220&254, purity 100%,MS ESI calcd. For C₂₆H₃₁NO₂ [M+H]⁺ 396, found 396.

Example 4. Synthesis of Compound 4

Step 1 (Compound 4). To a solution of A2 (100 mg, 0.312 mmol) in DCM (5mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at25° C. The mixture was stirred at 25° C. for 30 mins.N-methyl-1-phenylmethanamine (60.4 mg, 0.499 mmol) was added. Themixture was stirred at 25° C. for 1 hour. Water (5 mL) was added. Themixture was extracted with DCM (2×5 mL), washed with brine, dried overNa₂SO₄, concentrated in vacuo to give a crude product which was purifiedby prep. HPLC (Column: Xtimate C18 150*25 mm*5 um; Conditions: water(0.05% ammonia hydroxide v/v)-ACN; Begin B: 57; End B: 87; 100% B HoldTime (min): 2.5; FlowRate(ml/min): 25; Injections: 8) to give a solutionof product in water/CH₃CN and concentrated in vacuo to give Compound 4(109 mg, 83%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.38-7.28 (m, 2H), 7.26-7.22 (m, 2H),7.16-7.09 (m, 1H), 5.11-4.83 (m, 1H), 4.40-4.17 (m, 1H), 2.99-2.90 (m,3H), 2.82-2.67 (m, 1H), 2.38-2.26 (m, 1H), 1.91-1.74 (m, 4H), 1.74-1.59(m, 4H), 1.54-1.36 (m, 5H), 1.36-1.30 (m, 3H), 1.29-1.20 (m, 6H),1.20-1.01 (m, 4H), 0.81 (s, 3H).

LCMS Rt=1.325 min in 2 min chromatography, 30-90 AB, purity 100%, MS ESIcalcd. For C₂₈H₄₂NO₂ [M+H]⁺ 424, found 424.

Example 5. Synthesis of Compound 5

Step 1 (Compound 5). To a solution of A2 (100 mg, 0.312 mmol) in DCM (5mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at25° C. The mixture was stirred at 25° C. for 1 hour. Piperidine (42.4mg, 0.449 mmol) was added. The mixture was stirred at 25° C. for 1 hour.Water (8 mL) was added. The mixture was extracted with DCM (2×10 mL),washed with brine, dried over Na₂SO₄, concentrated in vacuo. The residuewas triturated with acetonitrile (5 mL) at 25° C. to give Compound 5 (34mg, 28%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 3.65-3.40 (m, 4H), 2.75-2.64 (m, 1H),2.35-2.25 (m, 1H), 1.90-1.75 (m, 4H), 1.75-1.55 (m, 10H), 1.55-1.49 (m,5H), 1.49-1.18 (m, 10H), 1.18-1.05 (m, 3H), 0.72 (s, 3H).

LCMS Rt=1.896 min in 2.0 min chromatography, 30-90 CD_POS_E.M, purity100%, MS ESI calcd. for C₂₅H₄₂NO₂ [M+H]⁺ 388, found 388.

Example 6. Synthesis of Compound 6

Step 1 (Compound 6). To a solution of A2 (150 mg, 0.468 mmol) in DCM (6mL) was added TEA (236 mg, 2.34 mmol) and HATU (266 mg, 0.7 mmol) at 25°C. After stirring at 25° C. for 30 mins, 1,4-oxazepane (75.6 mg, 0.748mmol) was added. The mixture was stirred at 25° C. for 1 h and quenchedwith water (8 mL). The mixture was extracted with DCM (2×8 mL). Theorganic layers were washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated in vacuo to give a crude product, which waspurified by prep. HPLC (Column: Waters Xbridge (150 mm*25 mm, 5 um)),gradient: 60-90% B (A=10 mM NH₄HCO₃/H₂O, B=MeCN), flow rate: 25 mL/min)to give a solid. The solid was treated water (5 mL), warmed to 80° C.and stirred for 2 h, filtered and concentrated to give Compound 6 (32mg).

¹H NMR (400 MHz, CDCl₃) δ 4.02-3.92 (m, 1H), 3.90-3.65 (m, 4H),3.65-3.62 (m, 1H), 3.52-3.35 (m, 2H), 2.73-2.59 (m, 1H), 2.35-2.18 (m,1H), 2.05-1.78 (m, 6H), 1.78-1.60 (m, 5H), 1.51-1.38 (m, 5H), 1.36-1.18(m, 9H), 1.18-1.02 (m, 3H), 0.80-0.70 (s, 3H).

LCMS Rt=0.863 min in 2.0 min chromatography, 30-90AB, purity 100%, MSESI calcd. for C₂₅H₄₂NO₃ [M+H]⁺ 404, found 404.

Example 7. Synthesis of Compound 7

Step 1 (Compound 7). To a solution of A2 (80 mg, 0.25 mmol) in DCM (3mL) was added TEA (125 mg, 1.24 mmol) and HATU (142 mg, 0.37 mmol) at25° C. After stirring at 25° C. for 30 mins, N-methylaniline (42.7 mg,0.40 mmol) was added. The mixture was stirred at 25° C. for 16 h andquenched with water (5 mL). The mixture was extracted with DCM (2×4 mL).The organic phase was washed with brine (2×8 mL), dried over Na₂SO₄,filtered, concentrated in vacuo to give a crude product which waspurified by prep. HPLC (Column: Xtimate C18 150*25 mm*5 um;Conditions:water (0.05% ammonia hydroxide v/v)-ACN, 61%-91% B; GradientTime (min): 10; 100% B Hold Time (min): 2.5; FlowRate(ml/min): 25) togive a solid, which was triturated with MeCN (5 mL) at 25° C. for 4hours to give Compound 7 (14 mg, 14%) as a solid.

1H NMR (400 MHz, CDCl₃) δ 7.50-7.40 (m, 2H), 7.40-7.30 (m, 1H),7.15-7.05 (m, 2H), 3.26 (s, 3H), 2.50-2.40 (m, 1H), 2.15-2.00 (m, 1H),1.90-1.60 (m, 6H), 1.50-1.20 (m, 14H), 1.10-0.75 (m, 8H), 0.65-0.50 (m,1H).

LCMS Rt=1.036 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. For C₂₇H₄₀NO₂ [M+H]⁺ 410.

Example 8. Synthesis of Compound 8

Step 1 (Compound 8). To a solution of A2 (100 mg, 0.312 mmol) in DCM (4mL) was added TEA (156 mg, 1.55 mmol) and HATU (112 mg, 0.468 mmol) at25° C. After stirring at 25° C. for 30 minutes, cyclohexanamine (49.4mg, 0.499 mmol) was added. The mixture was stirred at 25° C. for 16 hrs,quenched with water (4 mL) and extracted with DCM (2×4 mL). The organiclayers were washed with brine (2×5 mL), dried over Na₂SO₄, filtered,concentrated in vacuo to give a crude product, which was purified bysilica gel chromatography eluted with PE/EtOAc=3/1 to afford a impureproduct. The impure product was re-crystallized (85° C.) from MeCN (2mL) and water (20 mL) to give Compound 8 (86 mg, 69%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.20-5.05 (m, 1H), 3.85-3.70 (m, 1H),2.25-2.10 (m, 1H), 2.09-2.00 (m, 1H), 1.95-1.55 (m, 12H), 1.54-1.30 (m,8H), 1.29-1.00 (m, 16H), 0.66 (s, 3H).

LCMS Rt=1.176 min in 2.0 min chromatography, 30-90 AB, purity 100%, MSESI calcd. for C₂₆H₄₄NO₂ [M+H]⁺ 402, found 402.

Example 9. Synthesis of Compound 9

Step 1. (Compound 9). To a solution of A2 (100 mg, 0.312 mmol) in DCM (4mL) was added TEA (156 mg, 1.55 mmol) and HATU (112 mg, 0.468 mmol) at25° C. After stirring at 25° C. for 30 minutes, N-methylcyclohexanamine(56.4 mg, 0.499 mmol) was added. The mixture was stirred at 25° C. for16 hrs, quenched with water (4 mL) and extracted with DCM (2×4 mL). Theorganic layers were washed with brine (2×5 mL), dried over Na₂SO₄,filtered, concentrated in vacuo to give a crude product, which waspurified by silica gel chromatography eluted with PE/EtOAc=3/1 to give asolid, which was lyophilized to give Compound 9 (44 mg, 34%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 4.55-4.45 (m, 0.5H), 3.80-3.70 (m, 0.5H),2.90-2.70 (m, 3H), 2.69-2.60 (m, 1H), 2.35-2.20 (m, 1H), 1.90-1.50 (m,15H), 1.49-1.15 (m, 18H), 1.14-1.00 (m, 3H), 0.73 (s, 3H).

LCMS Rt=1.239 min in 2.0 min chromatography, 30-90 AB, purity 100%, MSESI calcd. for C₂₇H₄₆NO₂ [M+H]⁺ 416, found 416.

Example 10. Synthesis of Compound 10

To a solution of A2 (100 mg, 0.312 mmol) in DCM (4 mL) was added TEA(156 mg, 1.55 mmol) and HATU (112 mg, 0.468 mmol) at 25° C. Afterstirring at 25° C. for 30 minutes, N-methyltetrahydro-2H-pyran-4-amine(57.4 mg, 0.499 mmol) was added. The mixture was stirred at 25° C. for16 hrs, quenched with water (4 mL) and extracted with DCM (2×4 mL). Theorganic layers were washed with brine (2×5 mL), dried over Na₂SO₄,filtered, concentrated in vacuo to give a crude product, which waspurified by silica gel chromatography eluted with PE/EtOAc=3/1 to affordthe desired compound. The compound was lyophilized to give a solid (80mg) that was further re-crystallized (85° C.) from MeCN (2 mL) and water(20 mL) to give Compound 10 (66 mg, 51%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 4.85-4.70 (m, 0.5H), 4.15-3.95 (m, 2H),3.55-3.40 (m, 1.5H), 2.90-2.70 (m, 3H), 2.69-2.60 (m, 1H), 2.35-2.20 (m,1H), 1.90-1.60 (m, 10H), 1.59-1.16 (m, 18H), 1.15-1.00 (m, 3H), 0.72 (s,3H).

LCMS Rt=1.005 min in 2.0 min chromatography, 30-90 AB, purity 100%, MSESI calcd. for C₂₆H₄₄NO₃ [M+H]⁺ 418, found 418.

Example 11. Synthesis of Compound 11

Step 1 (Compound 1). To a solution of A2 (100 mg, 0.312 mmol) in DCM (5mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at25° C. After stirring at 25° C. for 30 minutes, pyridin-4-ylmethylamine(50.6 mg, 0.468 mmol) was added. The mixture was stirred at 25° C. for 1h. Water (20 mL) was added. The mixture was extracted with DCM (2×20mL), washed with brine (20 mL), dried over Na₂SO₄, concentrated in vacuoto give a crude product, which was purified by flash column (0˜30% ofEtOAc in PE) to give Compound 11 (68 mg, 53%) as a solid. ¹H NMR (400MHz, CDCl₃) δ 8.56 (d, J=4.0 Hz, 2H), 7.20 (d, J=4.0 Hz, 2H), 5.68 (brs, 1H), 4.51 (d, J=8 Hz, 1H), 4.44 (d, J=8 Hz, 1H), 2.22-2.15 (m, 2H),1.91-1.79 (m, 5H), 1.75-1.62 (m, 3H), 1.50-1.37 (m, 6H), 1.35-1.23 (m,8H), 1.18-1.08 (m, 4H), 0.71 (s, 3H).

LCMS Rt=1.453 min in 3.0 min chromatography, 10-80AB, purity 100%, MSESI calcd. for C₂₆H₃₉N₂O₂ [M+H]⁺ 411, found 411.

Example 12. Synthesis of Compound 12

Step 1 (Compound 12)

To a solution of A2 (100 mg, 0.312 mmol) in DCM (5 mL) was added TEA(156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25° C. Afterstirring at 25° C. for 30 minutes, pyridin-3-ylmethylamine (50.6 mg,0.468 mmol) was added. The mixture was stirred at 25° C. for 1 h. Water(20 mL) was added. The mixture was extracted with DCM (2×20 mL), washedwith brine (20 mL), dried over Na₂SO₄, concentrarted in vacuo to give acrude product, which was purified by flash column (0˜30% of EtOAc in PE)to give Compound 12 (63 mg, 49%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.55-8.53 (m, 2H), 7.65 (d, J=8.0 Hz, 1H),7.27 (d, J=8.0 Hz, 1H), 5.63-5.61 (m, 1H), 4.57-4.39 (m, 2H), 2.22-2.11(m, 2H), 1.89-1.74 (m, 5H), 1.72-1.61 (m, 3H), 1.49-1.36 (m, 6H),1.31-1.19 (m, 8H), 1.17-1.02 (m, 4H), 0.68 (s, 3H)

LCMS Rt=2.016 min in 4.0 min chromatography, 10-80AB, purity 100%, MSESI calcd. for C₂₆H₃₉N₂O₂ [M+H]⁺ 411, found 411.

Example 13. Synthesis of Compound 13

To a solution of A2 (100 mg, 0.312 mmol) in DCM (5 mL) was added TEA(156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25° C. Afterstirring at 25° C. for 30 mins, N-methyl-1-(pyridin-4-yl)methylamine(57.1 mg, 0.468 mmol) was added. The mixture was stirred at 25° C. for 1h, quenched with water (20 mL) and extracted with DCM (2×20 mL). Theorganic layers were washed with brine (20 mL), dried over Na₂SO₄,concentrated in vacuo to give a crude product, which was purified byflash silica gel chromatography (0˜30% of EtOAc in PE) to give Compound13 (81 mg, 61%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.59-8.54 (m, 2H), 7.15 (d, J=4.0 Hz, 1.4H),7.07 (d, J=4.0 Hz, 0.6H), 5.00 (d, J=20 Hz, 0.3H), 4.89 (d, J=16 Hz,0.7H), 4.37-4.26 (m, 1H), 3.03 (s, 2.2H), 2.96 (m, 0.8H), 2.81 (t, J=12Hz 0.8H), 2.56 (t, J=12 Hz 0.2H) 2.34-2.26 (m, 1H), 1.81-1.74 (m, 4H),1.72-1.61 (m, 3H), 1.52-1.21 (m, 16H), 1.13-1.11 (m, 3H), 0.79 (s, 3H)

LCMS Rt=1.491 min in 3.0 min chromatography, 10-80AB, purity 100%, MSESI calcd. for C₂₇H₄₁N₂O₂[M+H]⁺ 425, found 425.

Example 14. Synthesis of Compound 14

To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) was added TEA(156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25° C. Afterstirring at 25° C. for 30 minutes,N-methyl-1-(tetrahydro-2H-pyran-4-yl)methylamine (64.4 mg, 0.499 mmol)was added. The mixture was stirred at 25° C. for 16 hrs, quenched withwater (15 mL) and extracted with DCM (2×10 mL). The organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated in vacuoto give a crude product, which was purified by flash silica gelchromatography (0˜40% of EtOAc in PE) to give Compound 14 (31 mg, 23%)as a solid.

¹H NMR (400 MHz, CDCl₃) δ 4.05-3.91 (m, 2H), 3.69-3.53 (m, 1H),3.45-3.27 (m, 2H), 3.10-3.03 (m, 2H), 3.02-2.89 (m, 2H), 2.77-2.65 (m,1H), 2.32-2.16 (m, 1H), 1.99-1.73 (m, 5H), 1.73-1.60 (m, 4H), 1.60-1.56(m, 1H), 1.55-1.47 (m, 2H), 1.46-1.35 (m, 6H), 1.35-1.18 (m, 10H),1.17-1.025 (m, 3H), 0.74 (s, 3H).

LCMS Rt=1.013 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. For C₂₇H₄₆NO₃ [M+H]⁺ 432, found 432.

Example 15. Synthesis of Compound 15

To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) was added TEA(156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25° C. Afterstirring at 25° C. for minutes, pyridin-2-ylmethylamine (53.9 mg, 0.499mmol) was added. The mixture was stirred at 25° C. for 16 hrs, quenchedwith water (15 mL) and extracted with DCM (2×10 mL). The organic layerswere washed with brine, dried over Na₂SO₄, concentrated in vacuo to give110 mg of crude product, which was purified by prep. HPLC (Column:Kromasil 150*25 mm*10 um; Conditions: water (0.05% ammonia hydroxidev/v)-ACN; Begin B: 40; End B: 70; Gradient Time (min): 8; 100% B HoldTime (min): 2; FlowRate(ml/min): 30; Injections: 6) and concentrated invacuo to give Compound 15 (26 mg, 24%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.58-8.50 (m, 1H), 7.70-7.62 (m, 1H),7.30-7.27 (m, 1H), 7.21-7.16 (m, 1H), 6.64-6.48 (m, 1H), 4.62-4.53 (m,2H), 2.30-2.16 (m, 1H), 2.03-1.95 (m, 1H), 1.89-1.76 (m, 4H), 1.74-1.59(m, 4H), 1.50-1.36 (m, 6H), 1.34-1.26 (m, 7H), 1.25-0.99 (m, 5H), 0.67(s, 3H).

LCMS Rt=0.601 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. For C₂₆H₃₉N₂O₂ [M+H]⁺ 411, found 411.

Example 16. Synthesis of Compound 16

To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) was added TEA(156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25° C. Afterstirring at 25° C. for 30 minutes, N-methyl-1-(pyridin-3-yl)methylamine(60.9 mg, 0.499 mmol) was added. The mixture was stirred at 25° C. for16 hrs, quenched with water (15 mL) and extracted with DCM (2×10 mL).The combined organic layers were washed with brine, dried over Na₂SO₄,concentrated in vacuo to give 120 mg of crude product, which waspurified by prep. HPLC (Column: Kromasil 150*25 mm*10 um; Conditions:water (0.05% ammonia hydroxide v/v)-ACN; Begin B: 40; End B: 70;Gradient Time (min): 8; 100% B Hold Time (min): 2; FlowRate(ml/min): 30;Injections: 5) and concentrated to give Compound 16 (6 mg, 5%) as asolid. The NMR of the compound shows rotamers.

¹H NMR (400 MHz, CDCl₃) δ 8.60-8.44 (m, 2H), 7.66-7.41 (m, 1H),7.31-7.26 (m, 1H), 5.00-4.90 (m, 0.2H), 4.90-4.76 (m, 0.8H), 4.36-4.28(m, 0.8H), 4.28-4.20 (m, 0.2H), 2.94 (s, 2.4H), 2.85 (s, 0.6H),2.75-2.67 (m, 0.8H), 2.67-2.60 (m, 0.2H), 2.35-2.23 (m, 1H), 1.87-1.62(m, 9H), 1.51-1.38 (m, 6H), 1.36-1.27 (m, 5H), 1.25-1.19 (m, 2H),1.15-1.05 (m, 3H), 0.83-0.71 (m, 4H).

LCMS Rt=0.647 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. For C₂₇H₄₁N₂O₂ [M+H]⁺ 425, found 425.

Example 17. Synthesis of Compound

Step 1 (Compound 17). To a solution of A2 (100 mg, 0.312 mmol) in DCM (3mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at25° C. After stirring at 25° C. for 30 mins, cyclohexylmethanamine (56.4mg, 0.499 mmol) was added. The mixture was stirred at 25° C. for 16 hrsand treated with water (15 mL). The mixture was extracted with DCM (2×10mL). The organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to give a crude product, which was purified byflash silica gel chromatography (0˜30% of EtOAc in DCM) to give crudeCompound 17 (23 mg, 18%) as a solid. The crude product wasre-crystallized from MeOH (15 mL) to give Compound 17 (9 mg, 39%) as asolid.

¹H NMR (400 MHz, CDCl₃) δ 5.34-5.24 (m, 1H), 3.24-3.13 (m, 1H),3.09-2.97 (m, 1H), 2.23-2.12 (m, 1H), 2.12-2.06 (m, 1H), 1.94-1.79 (m,4H), 1.77-1.61 (m, 9H), 1.50-1.34 (m, 8H), 1.32-1.20 (m, 9H), 1.19-1.03(m, 5H), 0.98-0.87 (m, 2H), 0.68 (s, 3H).

LCMS Rt=1.197 min in 2 min chromatography, 30-90 AB, purity 100%, MS ESIcalcd. For C₂₇H₄₆NO₂ [M+H]⁺ 416, found 416.

Example 18. Synthesis of Compound 18

Step 1 (Compound 18). To a solution of A2 (100 mg, 0.312 mmol) in DCM (5mL) was added TEA (213 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at25° C. After stirring at 25° C. for 30 mins, N-methyl-2-phenylethanamine(63.2 mg, 0.468 mmol) was added. The mixture was stirred at 25° C. for 1h, treated with water (20 mL) and extracted with DCM (2×20 mL). Theorganic layers were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated in vacuo to give a crude product, which waspurified by flash silica gel chromatography (0˜30% of EtOAc in PE) togive Compound 18 (39 mg, 29%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.37-7.26 (m, 2H), 7.26-7.12 (m, 3H),4.00-3.83 (m, 1H), 3.42-3.23 (m, 1H), 2.94-2.97 (m, 3H), 2.87-2.76 (m,2H), 2.67 (t, J=8.0 Hz, 0.6H), 2.43 (t, J=8.0 Hz, 0.4H), 2.31-2.08 (m,1H), 1.88-1.75 (m, 3H), 1.71-1.58 (m, 4H), 1.50-1.30 (m, 7H), 1.30-0.97(m, 12H), 0.68-0.70 (m, 3H).

LCMS Rt=3.174 min in 4.0 min chromatography, 10-80AB, purity 100%, MSESI calcd. for C₂₉H₄₄NO₂ [M+H]⁺ 438, found 438.

Example 19. Synthesis of Compound 19

Step 1 (Compound 19). To a solution of A2 (100 mg, 0.312 mmol) in DCM (5mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at25° C. The mixture was stirred at 25° C. for 30 mins. 2-phenylethanamine(37.8 mg, 0.312 mmol) was added. The mixture was stirred at 25° C. for12 hrs, treated with water (20 mL) and extracted with DCM (2×20 mL). Theorganic layers were washed with brine (20 mL), dried over Na₂SO₄,concentrated in vacuo to give a crude product, which was purified byflash silica gel chromatography (0˜30% of EtOAc in PE) to give Compound19 (21 mg, 16%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.33-7.28 (m, 2H), 7.25-7.18 (m, 3H),5.25-5.20 (m, 1H), 3.66-3.60 (m, 1H), 3.51-3.42 (m, 1H), 2.82 (t, J=8.0Hz, 2H), 2.19-2.08 (m, 1H), 2.05-2.00 (m, 1H), 1.86-1.76 (m, 3H),1.74-1.59 (m, 5H), 1.48-1.32 (m, 7H), 1.30-1.22 (m, 6H), 1.15-1.00 (m,5H), 0.62 (s, 3H).

LCMS Rt=2.344 min in 4.0 min chromatography, 30-90AB, purity 98.4%, MSESI calcd. for C₂₈H₄₂NO₂ [M+H]⁺ 424, found 424.

Example 20. Synthesis of Compound 20

Step 1 (Compound 20). To a solution of A2 (100 mg, 0.312 mmol) in DMF (5mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at25° C. The mixture was stirred at 25° C. for 30 mins.(R)-1-phenylethanamine (56.7 mg, 0.468 mmol) was added. The mixture wasstirred at 25° C. for 12 hrs, treated with water (20 mL) and extractedwith DCM (2×20 mL). The organic layers were washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated in vacuo to give a crudeproduct, which was purified by flash silica gel chromatography (0˜30% ofEtOAc in PE) to give Compound 20 (51 mg, 39%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.39-7.30 (m, 4H), 7.29-7.27 (m, 1H),5.45-5.42 (m, 1H), 5.22-5.14 (m, 1H), 2.25-2.14 (m, 1H), 2.08 (t, J=8.0Hz, 1H), 1.97-1.91 (m, 1H), 1.89-1.79 (m, 3H), 1.77-1.62 (m, 4H), 1.50(d, J=4.0 Hz, 3H), 1.47-1.34 (m, 6H), 1.32-1.20 (m, 8H), 1.18-1.04 (m,4H), 0.71 (s, 3H).

LCMS Rt=3.095 min in 4.0 min chromatography, 10-80AB, purity 100%, MSESI calcd. for C₂₈H₄₂NO₂ [M+H]⁺ 424, found 424.

Example 21. Synthesis of Compound 21

Step 1 (Compound 21). To a solution of A2 (100 mg, 0.312 mmol) in DMF (4mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at25° C. After stirring at 30° C. for 30 mins,(S))-N-methyl-1-phenylethanamine (63.2 mg, 0.468 mmol) was added. Themixture was stirred at 30° C. for 16 h then treated with water (8 mL).The precipitate was collected by filtration and purified by HPLC (WatersXbridge 150*25 5 u, water (10 mM NH₄HCO₃)-ACN, gradient: 55-85% B, flowrate: 25 mL/min) to give Compound 21 (40 mg, 30%) as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.40-7.32 (m, 2H), 7.21-7.29 (m, 3H),6.02-5.72 (m, 1H), 3.94-3.81 (m, 1H), 3.15-2.98 (m, 3H), 2.90-2.81 (m,1H), 2.71-2.62 (m, 3H), 2.38-2.11 (m, 1H), 1.82-1.57 (m, 8H), 1.57-1.20(m, 10H), 1.19-1.01 (s, 7H), 0.74 (s, 3H).

LCMS Rt=1.174 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₉H₄₄NO₂ [M+H]⁺ 438, found 438.

Example 22. Synthesis of Compound 22

Step 1 (Compound 22). To a solution of A2 (100 mg, 0.312 mmol) in DMF (4mL) was added TEA (0.213 mL, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at30° C. After stirring at 30° C. for 30 mins, N-methyl-1-(pyridin-2-yl)methanamine (60.9 mg, 0.499 mmol) was added. The mixture was stirred at30° C. for 16 h, treated with water (8 mL), filtered and concentrated.The crude product was purified by HPLC (Waters Xbridge 150*25 5 u, water(10 mM NH₄HCO₃)-ACN, gradient: 40-70% B, flow rate: 25 mL/min) to giveCompound 22 (13 mg, 10%) as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.58-8.48 (m, 1H), 7.81-7.70 (m, 1H),7.30-7.18 (m, 2H), 5.10-4.70 (m, 1H), 4.49-4.45 (m, 1H), 3.95-3.78 (m,1H), 2.98-2.80 (m, 3H), 2.20-2.05 (m, 3H), 1.85-1.71 (m, 5H), 1.71-1.57(m, 5H), 1.49-1.19 (m, 5H), 1.19-1.10 (m, 5H), 1.10-0.98 (m, 4H), 0.70(s, 3H).

LCMS Rt=0.668 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₇H₄₁N₂O₂ [M+H]⁺ 425, found 425.

Example 23. Synthesis of Compound 23

Step 1 (Compound 23). To a solution of A2 (100 mg, 0.312 mmol) in DCM (2mL) was added HATU (177 mg, 0.468 mmol), TEA (0.213 mL, 1.55 mmol) andazepane (108 mg, 1.09 mmol) at 25° C. After stirring at 25° C. for 24hrs, the mixture was poured into water (200 mL) and extracted with DCM(2×200 mL). The combined organic layers were washed with brine (100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography on silica gel (petroleum ether/ethylacetate=0:1) and lyophilized to afford Compound 23 (78 mg, 62%) as asolid.

¹H NMR (400 MHz, CDCl₃) δ 3.90-3.70 (m, 2H), 3.30-3.15 (m, 2H),2.70-2.60 (m, 1H), 2.25-2.15 (m, 1H), 1.85-1.55 (m, 13H), 1.54-1.45 (m,8H), 1.44-1.05 (m, 13H), 0.76 (s, 3H).

LCMS Rt=1.121 min in 2 min chromatography, 30-90 AB, purity 98%, ESIcalcd. for C₂₆H₄₄NO₂ [M+H]⁺ 402, found 402.

Example 24. Synthesis of Compound 24

Step 1 (Compound 24). To a solution of A2 (100 mg, 0.312 mmol) in DCM (2mL) was added HATU (177 mg, 0.468 mmol), TEA (0.213 mL, 1.55 mmol) and(tetrahydro-2H-pyran-4-yl) methanamine (125 mg, 1.09 mmol) at 25° C.After stirring at 25° C. for 12 hrs, the mixture was poured into water(200 mL) and extracted with DCM (2×200 mL). The combined organic layerswere washed with brine (100 mL), dried over anhydrous Na₂SO₄, filteredand concentrated. The residue was purified by column chromatography onsilica (petroleum ether/ethyl acetate=0:1) and lyophilized to affordCompound 24 (48 mg, 37%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.40-5.30 (m, 1H), 4.05-3.90 (m, 2H),3.40-3.30 (m, 2H), 3.25-3.15 (m, 1H) 3.10-3.00 (m, 1H), 2.15-2.05 (m,2H), 1.90-1.55 (m, 12H), 1.50-1.00 (m, 19H), 0.67 (s, 3H).

LCMS Rt=0.934 min in 2 min chromatography, 30-90 AB, purity 97%, ESIcalcd. for C₂₆H₄₄NO₃ [M+H]⁺ 418, found 418.

Example 25. Synthesis of Compound 25

Step 1 (Compound 25) To a solution of A2 (100 mg, 0.312 mmol) in DCM (4mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at25° C. After stirring for 30 mins, (R)-2-methylpiperidine (60.4 mg,0.499 mmol) was added to the reaction mixture. The reaction mixture wasstirred at 25° C. for 2 hours. The reaction mixture was diluted withwater (10 mL), extracted with EtOAc (3×10 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was triturated with EtOAc (10 mL) and n-hexane (10mL) to give Compound 25 (23 mg, 18%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.11-3.76 (m, 2H), 3.31-2.99 (m, 1H),2.77-2.54 (m, 1H), 2.42-2.26 (m, 1H), 1.88-1.74 (m, 3H), 1.73-1.53 (m,10H), 1.51-1.20 (m, 17H), 1.19-1.10 (m, 5H), 0.70-0.65 (m, 3H)

LCMS, Rt=1.113 min in 2.0 min chromatography, 30-90AB, purity 97.674%,MS ESI calcd. For C₂₆H₄₄NO₂ [M+H]⁺ 402, found 402.

Example 26. Synthesis of Compound 26

Step 1 (Compound 26). To a solution of A2 (100 mg, 0.312 mmol) in DCM (4mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at25° C. The mixture was stirred at 25° C. for 30 mins.1-cyclohexyl-N-methylmethanamine (60.4 mg, 499 mmol) was added to thereaction mixture. The reaction mixture was stirred at 25° C. for 2 hrs.The residue was diluted with water (10 mL), extracted with EtOAc (3×10mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (PE/EtOAc=3/1 to 1/1) to afford Compound 26 (76 mg, 57%)as a solid.

¹H NMR (400 MHz, CDCl₃) δ 3.62-3.49 (m, 1H), 3.02 (s, 1H), 2.93-2.85 (m,2H), 2.77-2.65 (m, 1H), 2.32-2.19 (m, 1H), 1.88-1.58 (m, 14H), 1.50-1.23(m, 15H), 1.23-0.81 (m, 9H), 0.73 (m, 3H).

LCMS Rt=1.228 min in 2.0 min chromatography, 30-90AB, purity 100%, MSESI calcd. for C₂₈H₄₈NO₂ [M+H]⁺ 430, found 430.

Example 27. Synthesis of Compound 27

Step 1 (Compound 27). To a solution of A2 (100 mg, 0.312 mmol) in DCM (4mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at25° C. The mixture was stirred at 25° C. for 30 mins.(S)-1-phenylethanamine (60.4 mg, 0.499 mmol) was added to the reactionmixture. The reaction mixture was stirred at 25° C. for 2 hrs. Theresidue was diluted with water (10 mL) and extracted with EtOAc (3×10mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was triturated with EtOAc (10 mL) andn-hexane (10 mL) to give Compound 27 (28 mg, crude) as a solid, whichwas further purified by HPLC (Method: Column YMC-Actus Triart C18 100*30mm*5 um; Conditions: water (0.05% HCl)-ACN; Begin B: 60; End B: 90;Gradient Time (min): 9.5; 100% B Hold Time (min): 2.5; FlowRate(ml/min);25) to obtain Compound 27 (14 mg, 11%) as a solid.

HNMR (400 MHz, CDCl₃) δ 7.36-7.29 (m, 4H), 7.26-7.23 (m, 1H), 5.52-5.46(m, 1H), 5.19-5.10 (m, 1H), 2.23-2.05 (m, 1H), 1.87-1.59 (t, 8H),1.51-1.28 (m, 10H), 1.28-1.00 (m, 11H), 0.58 (s, 3H)

LCMS Rt=2.327 in in 4.0 min chromatography, 30-90AB, purity 99%, MS ESIcalcd. for C₂₈H₄₂NO₂ [M+H]⁺ 424, found 424.

Example 28. Synthesis of Compound 28

Step 1 (Compound 28). To a solution of A2 (100 mg, 0.312 mmol) in DCM (3mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at25° C. The mixture was stirred at 25° C. for 30 mins.(S)-2-methylpiperidine (46.4 mg, 0.468 mmol) was added. The mixture wasstirred at 25° C. for 16 hrs. The reaction mixture was quenched withwater (10 mL and extracted with DCM (2×10 mL). The combined organiclayers were washed with brine (20 mL), dried over Na₂SO₄, concentratedin vacuo to give a crude product which was purified by flash silica gelchromatography (0˜30% of EtOAc in PE) to give Compound 28 (18 mg, 14%)as a solid.

¹H NMR (400 MHz, DMSO-d₆, t=80° C.) δ 4.80-4.47 (m, 1H), 4.18-3.83 (m,2H), 2.99-2.82 (m, 1H), 2.79-2.69 (m, 1H), 2.21-2.02 (m, 2H), 1.82-1.57(m, 9H), 1.56-1.46 (m, 3H), 1.45-1.18 (m, 11H), 1.17-0.96 (m, 10H), 0.67(s, 3H).

LCMS Rt=1.123 min in 2 min chromatography, 30-90 AB, purity 100%, MS ESIcalcd. For C₂₆H₄₄NO₂ [M+H]⁺ 402, found 402.

Example 29. Synthesis of Compound 29

Step 1 (Compound 29). To a solution of A2 (100 mg, 0.312 mmol) in DCM (3mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at25° C. After stirring at 25° C. for 30 mins, tetrahydro-2H-pyran-4-amine(47.3 mg, 0.468 mmol) was added. The mixture was stirred at 25° C. for16 hrs and treated with water (10 mL). The mixture was extracted withDCM (2×10 mL). The combined organic layers were washed with brine (20mL), dried over Na₂SO₄, concentrated in vacuo to give a crude product,which was purified by flash silica gel chromatography (0˜5% of MeOH inDCM) to give a solid. The crude residue (113 mg) was then trituratedwith MTBE (8 mL) at 15° C. to give Compound 29 (80 mg, 71%) as a solid.The compound was dissolved in DCM (30 mL) and the solution was washedwith citric acid (2×20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give a crude product. The crude product wasdissolved in MeCN/H₂O=1/2 (30 mL), concentrated in vacuo to remove mostof MeCN and lyophilized to give Compound 29 (42 mg, 33%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.19-5.08 (m, 1H), 4.09-3.99 (m, 1H),3.98-3.90 (m, 2H), 3.55-3.44 (m, 2H), 2.23-2.11 (m, 1H), 2.10-2.03 (m,1H), 1.96-1.80 (m, 6H), 1.79-1.62 (m, 4H), 1.52-1.39 (m, 8H), 1.34-1.23(m, 8H), 1.19-1.04 (m, 4H), 0.67 (s, 3H).

LCMS Rt=0.902 min in 2 min chromatography, 30-90 AB, purity 100%, MS ESIcalcd. For C₂₅H₄₂NO₃ [M+H]⁺ 404, found 404.

Example 30. Synthesis of Compound 30

Step 1 (Compound 30). To a solution of A2 (100 mg, 0.312 mmol) in DCM (3mL) was added HATU (177 mg, 0.468 mmol) and Et₃N (156 mg, 1.55 mmol) at25° C. After stirring at 25° C. for 0.5 hour, (S)-3-phenylpyrrolidine(73.4 mg, 0.499 mmol) was added. The reaction mixture was stirred at 40°C. for 10 hours, treated by water (10 mL) and extracted with EtOAc (2×10mL). The combined organic phase was washed with water (2×10 mL) andsaturated brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0-30% of EtOAcin PE) to give Compound 30 (31 mg, 22%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.37-7.29 (m, 2H), 7.28-7.21 (m, 3H),4.14-3.68 (m, 2H), 3.59-3.27 (m, 3H), 2.61-2.49 (m, 1H), 2.39-2.16 (m,2H), 2.11-1.91 (m, 1H), 1.89-1.64 (m, 9H), 1.49-1.31 (m, 9H), 1.29-1.24(m, 5H), 1.15-1.02 (m, 3H), 0.85-0.78 (m, 3H).

LCMS Rt=1.095 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₃₀H₄₄NO₂ [M+H]⁺ 450, found 450.

SFC Rt=9.574 min in 15 min chromatography, IC_ETOH(DEA)_40_2,5ML_15MIN,99% de. (Column: Chiralpak IC-3 150×4.6 mm I.D., 3 um; Mobile phase: 40%of ethanol (0.05% DEA) in CO₂.

Flow rate: 2.5 mL/min Column temperature: 40° C.).

Example 31. Synthesis of Compound 31

Step 1 (Compound 31) To a solution of A2 (100 mg, 0.312 mmol) in DCM (3mL) was added HATU (177 mg, 0.468 mmol) and Et₃N (156 mg, 1.55 mmol) at25° C. After stirring at 25° C. for 0.5 hour, (R)-3-phenylpyrrolidine(73.4 mg, 0.499 mmol) was added at 25° C. The reaction mixture wasstirred at 40° C. for 10 hrs and quenched with ice-water (10 mL). Theaqueous phase was extracted with EtOAc (3×20 mL). The combined organicphase was washed with brine (2×10 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by HPLC (Instrument:BQ; Method: Column YMC-Actus Triart C18 100*30 mm*5 um; Conditions:water (0.05% HCl)-ACN; Gradient 80%-100% B; Gradient Time (min): 9.5) toobtain Compound 31 (8 mg, 6%) as a solid.

HNMR (400 MHz, CDCl₃) δ 7.37-7.29 (m, 2H), 7.26-7.21 (m, 2H), 4.04-3.93(m, 1H), 3.82-3.70 (m, 1H), 3.66-3.28 (m, 3H), 2.64-2.50 (m, 1H),2.39-2.18 (m, 2H), 2.08-1.95 (m, 1H), 1.90-1.62 (m, 8H), 1.54-1.22 (m,17H), 1.13-1.05 (m, 2H), 0.79 (s, 3H).

LCMS Rt=1.090 min in 2.0 min chromatography, 30-90AB, purity 100%; ESIcalcd. For C₃₀H₄₄NO₂ [M+H]⁺ 450, found 450.

SFC Rt=11.297 min in 15 min chromatography. IC_ETOH(DEA) 40_2.5ML_15MIN,100% de.(Column: Chiralpak IC-3 150×4.6 mm I.D., 3 um; Mobile phase: 40%of ethanol (0.05% DEA) in CO₂. Flow rate: 2.5 mL/min Column temperature:40° C.).

Example 32. Synthesis of Compound 32

Step 1 (Compound 32). To a solution of A2 (200 mg, 0.624 mmol) in DCM (2mL) was added HATU (355 mg, 0.936 mmol) and TEA (125 mg, 1.24 mmol). Themixture was stirred at 25° C. for 20 min. To the mixture was added(R)-N-methyl-1-phenylethanamine (126 mg, 0.936 mmol). The mixture wasstirred at 25° C. for another 12 hours. The mixture was poured intowater (20 mL) and extracted with EtOAc (2×20 mL). The combined organiclayers were washed with brine (2×20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by HPLC(column: Xtimate C18 150*25 mm*5 um, gradient: 64-89% B, conditions:water (0.05% HCl)-ACN, flow rate: 30 mL/min) to give Compound 32 (50 mg)as a solid. The Compound 32 was further purified by SFC (Column: OD(250mm*30 mm, 5 um), Conditions: 0.1% NH₃H₂O ETOH, Gradient: from 35% to30%, FlowRate(ml/min): 50 mL/min, 25° C.) to afford Compound 32 (35 mg,13%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.37-7.23 (m, 5H), 6.18 (q, J=12.0 Hz, 1H),2.82-2.54 (m, 4H), 2.39-2.26 (m, 1H), 1.90-1.61 (m, 7H), 1.56 (s, 3H),1.50-1.20 (m, 16H), 1.16-1.05 (m, 3H), 0.81 (s, 3H).

LCMS Rt=0.952 min in 1.5 min chromatography, 5-95AB, purity 100%, MS ESIcalcd. for C₂₉H₄₄NO₂ [M+H]⁺ 438, found 438.

Example 33. Synthesis of Compound 33 and Compound 34

Step 1 (Compound 33 and Compound 34). To a solution of A2 (1 g, 3.12mmol) in DCM (10 mL) was added HATU (1.77 g, 4.68 mmol) and TEA (1.57 g,15.6 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 0.5hour. 1-(4-fluorophenyl)propan-1-amine (764 mg, 4.99 mmol) was added tothe reaction mixture at 25° C. The reaction mixture was stirred at 40°C. for 10 hours. The reaction mixture was treated with water (20 mL).The mixture was extracted with EtOAc (2×20 mL). The combined organicphase was washed with water (2×20 mL) and brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash silica gel chromatography (0˜25% of EtOAc in PE) to give Compound33 (Peak 1, 207 mg, 14%) and Compound 34 (Peak 2, 250 mg, 17%) as asolid.

(250 mg, 0.54 mmol) was further purified by flash column (0˜25% of EtOAcin PE) to give Compound 34 (150 mg,) as a light solid. Compound 34 Theimpure was re-purified by SFC (Chiralcel OJ 250*30 5 u), gradient:25-25% B (A=0.1% NH₃/H₂O, B=EtOH), flow rate: 60 mL/min) to giveCompound 34 (51 mg, 3%) as a solid.

Compound 33:

¹H NMR (400 MHz, CDCl3) δ 7.25-7.21 (m, 2H), 7.06-6.96 (m, 2H),5.46-5.38 (d, J=7.6 Hz, 1H), 4.93-4.82 (q, J=7.2 Hz, J=15.2 Hz, 1H),2.22-2.04 (m, 2H), 2.02-1.91 (m, 1H), 1.89-1.62 (m, 10H), 1.49-1.38 (m,6H), 1.37-1.30 (m, 2H), 1.28-1.26 (m, 4H), 1.22-1.03 (m, 5H), 0.92-0.87(t, J=7.2 Hz, 3H), 0.70 (s, 3H).

LCMS Rt=1.100 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₉H₄₃FNO₂ [M+H]⁺ 456, found 456.

SFC Rt=3.350 min in 10 min chromatography, OJ-H_EtOH(DEA)_5_40_2.5M,100% de. (Column: ChiralCel OJ-H 150×4.6 mm I.D., 5 um; Mobile phase: A:CO₂ B:Ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 5.5 min andhold 40% for 3 min, then 5% of B for 1.5 min; Flow rate: 2.5 mL/minColumn temperature: 40° C.).

SFC of a mixture of Compound 33 and Compound 34; Peak 1: Rt=3.121 minand Peak 2: Rt=3.372 min in 10 min chromatography, conditions:OJ-H_EtOH(DEA)_5_40_2.5M (Column: ChiralCel OJ-H 150×4.6 mm I.D., 5 umMobile phase: A: CO₂ B:Ethanol (0.05% DEA). Gradient: from 5% to 40% ofB in 5.5 min and hold 40% for 3 min, then 5% of B for 1.5 min Flow rate:2.5 mL/min Column temperature: 40° C.).

Compound 34

¹H NMR (400 MHz, CDCl₃) δ 7.25-7.21 (m, 2H), 7.04-6.96 (m, 2H),5.49-5.41 (d, J=8 Hz, 1H), 4.89-4.81 (q, J=7.6 Hz, J=15.2 Hz, 1H),2.22-2.07 (m, 2H), 1.88-1.61 (m, 10H), 1.49-1.29 (m, 7H), 1.28-1.23 (m,5H), 1.22-0.94 (m, 6H), 0.92-0.84 (t, J=7.2 Hz, 3H), 0.50 (s, 3H).

LCMS Rt=1.085 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₉H₄₃FNO₂ [M+H]⁺ 456, found 456.

SFC Rt=3.116 min in 10 min chromatography, OJ-H_EtOH(DEA)_5_40_2.5M,100% de. (Column: ChiralCel OJ-H 150×4.6 mm I.D., 5 um; Mobile phase: A:CO₂ B:Ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 5.5 min andhold 40% for 3 min, then 5% of B for 1.5 min; Flow rate: 2.5 mL/minColumn temperature: 40° C.).

Example 34. Synthesis of Compound 35

Step 1 (A3). To a solution of A2 (1 g, 3.12 mmol) in toluene (20 mL) wasadded 1,2-di(pyridin-2-yl)disulfane (1.37 g, 6.24 mmol) andtriphenylphosphine (1.63 g, 6.24 mmol). The mixture was stirred at 25°C. for 16 hrs. The reaction mixture was directly purified by a silicagel chromatography (PE/EtOAc=5/1) to give A3 (750 mg, 58%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.62-8.61 (m, 1H), 7.74-7.70 (m, 1H), 7.60 (d,J=8 Hz, 1H), 7.28-7.27 (m, 1H), 2.73 (t, J=8 Hz, 1H), 2.26-2.20 (m, 2H),1.89-1.71 (m, 7H), 1.49-1.27 (m, 10H), 1.26-1.24 (m, 4H), 1.19-1.03 (m,4H), 0.75 (s, 3H).

Step 2 (Compound 35). To a solution of A3 (100 mg, 0.242 mmol) in DCM (3mL) was added AgOTf (62.1 mg, 0.242 mmol), followed by1,2,3,4-tetrahydroquinoline (48.2 mg, 0.363 mmol) at 25° C. The mixturewas stirred at 25° C. for 16 hrs. The reaction mixture was filtered andthe residue was washed with DCM (15 mL). The combined organic layerswere washed with 1M HCl (10 mL), brine (30 mL), dried over Na₂SO₄,filtered and concentrated in vacuo to give Compound 35 (125 mg, crude)as an oil. The crude product was purified by HPLC (Column: YMC-ActusTriart C18 100*30 mm*5 um; Conditions: water(0.05% HCl)—CAN; Begin B:80; End B: 100; Gradient Time (min): 10; 100% B Hold Time (min): 1;FlowRate(ml/min): 25.) to afford Compound 35 (4 mg, 4%) as a solid.

LCMS Rt=1.126 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₉H₄₂NO₂ [M+H]⁺ 436, found 436.

¹H NMR (400 MHz, CDCl₃) δ 7.24-7.04 (m, 4H), 4.44-4.19 (m, 1H),3.40-3.10 (m, 2H), 2.82-2.58 (m, 2H), 2.37-2.01 (m, 3H), 1.86-1.70 (m,7H), 1.41-1.23 (m, 13H), 1.08-0.92 (m, 5H), 0.74 (s, 4H).

Example 35. Synthesis of Compound 36

Step 1 (Compound 36). To a solution of A3 (150 mg, 0.362 mmol) in DCM (3mL) was added AgOTf (93 mg, 0.362 mmol), followed by4-amino-3-methylbenzonitrile (71.7 mg, 0.543 mmol) at 25° C. Afterstirring the reaction at 25° C. for 1 hr, the reaction mixture wasfiltered and the residue was washed with DCM (15 mL). The combinedorganic layers were washed with 1M HCl (10 mL), brine (50 mL), driedover Na₂SO₄, filtered and concentrated in vacuo to give Compound 36 (130mg, crude) as an oil. The crude Compound 36 (125 mg, 0.2869 mmol) waspurified by HPLC (Method Column: YMC-Actus Triart C18 100*30 mm*5 um;Conditions: water(0.05% HCl)-ACN Begin B: 70; End B: 100; Gradient Time(min): 10; 100% B Hold Time (min): 1; FlowRate(ml/min): 25.) to affordCompound 36 (8 mg, 6%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.38-8.31 (m, 1H), 7.55-7.48 (m, 1H), 7.46 (s,1H), 6.96 (s, 1H), 2.40-2.22 (m, 5H), 2.09-1.99 (m, 1H), 1.88-1.75 (m,6H), 1.50-1.39 (m, 7H), 1.35-1.24 (m, 9H), 1.17-1.06 (m, 3H), 0.75 (s,3H).

LCMS Rt=1.081 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₈H₃₉N₂O₂ [M+H]⁺ 435, found 435.

Example 36. Synthesis of Compound 37

Step 1 (Compound 37). To a solution of A3 (150 mg, 0.362 mmol) in DCM (3mL) was added AgOTf (93 mg, 0.362 mmol), followed by adding2-amino-5-fluorobenzonitrile (73.9 mg, 0.543 mmol) at 25° C. Afterstirring the reaction at 25° C. for 1 hr, the reaction mixture wasfiltered and the residue was washed with DCM (15 mL). The combinedorganic layers were washed with 1M HCl (10 mL), brine (50 mL), driedover Na₂SO₄, filtered and concentrated in vacuo to give Compound 37 (136mg, crude) as an oil. The crude Compound 37 (125 mg, 0.2869 mmol) waspurified by HPLC (Method Column: YMC-Actus Triart C18 100*30 mm*5 um;Conditions: water(0.05% HCl)-ACN Begin B: 70; End B: 100; Gradient Time(min): 10; 100% B Hold Time (min): 1; FlowRate(ml/min): 25.) to affordCompound 37 (2 mg, 2%) as a solid.

LCMS Rt=1.044 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₇H₃₄FN₂O[M+H−H₂O]⁺ 421, found 421.

¹H NMR (400 MHz, CDCl₃) δ 8.48-8.40 (m, 1H), 7.49-7.42 (s, 1H),7.33-7.27 (m, 2H), 2.44-2.35 (m, 1H), 2.34-2.21 (m, 1H), 2.19-2.07 (m,1H), 1.93-1.71 (m, 6H), 1.52-1.37 (m, 7H), 1.36-1.21 (m, 9H), 1.19-1.01(m, 3H), 0.75 (s, 3H).

Example 37. Synthesis of Compound 38

The synthesis of B1 is disclosed in WO2014/169833.

Step 1 (Compound 38). To a solution of B1 (200 mg, 0.503 mmol) in DMF (5mL) was added aniline (56.2 mg, 0.604 mmol) and TEA (151 mg, 1.50 mmol)at 25° C. under N₂. The mixture was stirred at 25° C. for 18 h to give ayellow solution. The mixture was poured into saturated aqueous LiCl (50mL) and extracted with EtOAc (3×30 mL). The combined organic phase waswashed with saturated brine (2×50 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give a light solid, which was purified byprep-HPLC (Column: YMC-Actus Triart C18 150*30 5 u; Conditions: water(0.05% HCl)-ACN; Gradient 46%-76% B; Gradient Time (min): 8) andlyophilized to give Compound 38 (42.0 mg, 21%) as a light solid.

¹H NMR (400 MHz, CDCl₃) δ 7.25-7.15 (m, 2H), 6.72-6.68 (m, 1H),6.62-6.55 (m, 2H), 4.72-4.65 (m, 1H), 4.00-3.85 (m, 2H), 3.52-3.45 (m,1H), 2.60-2.53 (m, 1H), 2.30-2.15 (m, 1H), 2.00-1.55 (m, 8H), 1.50-1.20(m, 14H), 1.15-0.90 (m, 3H), 0.65 (s, 3H).

LCMS Rt=1.160 min in 2.0 min chromatography, 30-90 AB, purity 100%, MSESI calcd. for C₂₇H₄₀NO₂ [M+H]⁺ 410, found 410.

Example 38. Synthesis of Compound 39

Step 1 (Compound 39). To a solution of B1 (200 mg, 0.503 mmol) in DMFwas added N-methylaniline (64.6 mg, 0.604 mmol) and TEA (151 mg, 1.50mmol) at 25° C. under N₂. The mixture was stirred at 25° C. for 18 h togive a yellow solution. The mixture was poured into aqueous LiCl (50 mL,1N) and extracted with EtOAc (3×30 mL). The combined organic phase waswashed with saturated brine (2×50 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give a light solid. The crude product waspurified by pre-HPLC (Column: YMC-Actus Triart C18 150*30 5 u;Conditions: water(0.05% HCl)-ACN; Gradient 46%-76% B; Gradient Time(min): 8) to afford an the compound (50 mg, containing residue ofammonium salt) as a light solid. The product was dissolved in DCM (5 mL)and washed with aqueous NaHCO₃ (10 mL). The aqueous layer was extractedwith DCM (2×10 mL). The combined organic phase was dried over anhydrousNa₂SO₄, filtered and concentrated to give Compound 39 (21 mg, 10%) as alight solid.

¹H NMR (400 MHz, CDCl₃) δ 7.25-7.15 (m, 2H), 6.72-6.68 (m, 1H),6.62-6.55 (m, 2H), 4.10-3.98 (m, 2H), 3.00 (s, 3H), 2.62-2.53 (m, 1H),2.18-2.07 (m, 1H), 1.98-1.92 (m, 1H), 1.85-1.55 (m, 7H), 1.50-1.35 (m,7H), 1.35-1.18 (m, 8H), 1.18-1.00 (m, 3H), 0.67 (s, 3H).

LCMS Rt=1.182 min in 2.0 min chromatography, 30-90 AB, purity 100%, MSESI calcd. for C₂₈H₄₂NO₂ [M+H]⁺ 424, found 424.

Example 39. Synthesis of Compound 40

Step 1 (Compound 40). To a solution of B1 (100 mg, 0.251 mmol) in DMF (5mL) was added 4-fluoroaniline (33.4 mg, 0.301 mmol) and TEA (76.1 mg,0.753 mmol) at 25° C. under N₂. The mixture was stirred at 25° C. for 16h to give a yellow solution. The mixture was concentrated to give alight solid. The solid was purified by prep-HPLC (Column: PhenomenexGemini 150*25 mm*10 um; Conditions: water (0.05% HCl)-ACN; Gradient60%-100% B; Gradient Time (min): 10) to afford Compound 40 (25 mg, 23%)as a solid.

¹H NMR (400 MHz, CDCl₃) δ 6.95-6.86 (m, 2H), 6.68-6.60 (m, 2H),4.00-3.85 (m, 2H), 2.58-2.52 (m, 1H), 2.26-2.12 (m, 1H), 1.95-1.55 (m,9H), 1.50-1.14 (m, 15H), 1.14-0.96 (m, 3H), 0.63 (s, 3H).

LCMS Rt=0.962 min in 1.5 min chromatography, 5-95 AB, purity 100%, MSESI calcd. for C₂₇H₃₉FNO₂ [M+H]⁺ 428, found 428.

Example 40. Synthesis of Compound 41

Step 1 (Compound 41). To a solution of B1 (100 mg, 0.251 mmol) in DMF (5mL) was added 3-fluoroaniline (33.4 mg, 0.301 mmol) and TEA (76.1 mg,0.753 mmol) at 25° C. under N₂. The mixture was stirred at 25° C. for 16h to give a yellow solution. The mixture was concentrated to give alight solid. The solid was purified by prep-HPLC (Column: PhenomenexGemini 150*25 mm*10 um; Conditions: water (0.05% HCl)-ACN; Gradient60%-100% B; Gradient Time (min): 10) to afford Compound 41 (7 mg, 7%) asa solid.

¹H NMR (400 MHz, CDCl₃) δ 7.13-7.05 (m, 1H), 6.45-6.33 (m, 2H),6.30-6.22 (m, 1H), 3.96-3.83 (m, 2H), 2.58-2.52 (m, 1H), 2.26-2.12 (m,1H), 2.02-1.55 (m, 10H), 1.50-1.14 (m, 14H), 1.14-0.93 (m, 3H), 0.65 (s,3H).

LCMS Rt=0.988 min in 1.5 min chromatography, 5-95 AB, purity 100%, MSESI calcd. for C₂₇H₃₉FNO₂ [M+H]⁺ 428, found 428.

Example 41. Synthesis of Compound 42

Step 1 (Compound 42). To a suspension of diisopropylethylamine (42.1 mg,0.326 mmol) in DMF (5 mL) was added 3-fluoro-N-methylaniline (62.7 mg,0.502 mmol) at 25° C. under N₂. After stirring at 25° C. for 30 min, asolution of B1 (100 mg, 0.251 mmol) in DMF (5 mL) was added. The mixturewas stirred at 40° C. for 16 h to give a yellow solution. The mixturewas concentrated to give a product as a light yellow oil (150 mg,crude), which was purified by HPLC (Column: Phenomenex Gemini C18 250*5010 u; Conditions: water (0.05% ammonia hydroxide v/v)-ACN; Gradient80%-90% B; Gradient Time (min): 8) to afford Compound 42 (11 mg, 10%) asa solid.

¹H NMR (400 MHz, CDCl₃) δ 7.13-7.05 (m, 1H), 6.40-6.20 (m, 3H),4.08-3.98 (m, 2H), 2.98 (s, 3H), 2.60-2.50 (m, 1H), 2.22-2.08 (m, 1H),2.05-1.95 (m, 1H), 1.90-1.50 (m, 7H), 1.50-1.35 (m, 7H), 1.35-1.20 (m,8H), 1.20-1.00 (m, 3H), 0.67 (s, 3H).

LCMS Rt=1.197 min in 2.0 min chromatography, 30-90 AB, purity 100%, MSESI calcd. for C₂₈H₄₁FNO₂ [M+H]⁺ 442, found 442.

Example 42. Synthesis of Compound 43

Step 1 (Compound 43). To a solution of B1 (100 mg, 0.251 mmol) in DMF (5mL) was added 4-fluoro-N-methylaniline (37.6 mg, 0.301 mmol) and TEA(76.1 mg, 0.753 mmol) at 25° C. under N₂. The mixture was stirred at 25°C. for 16 h to give a yellow solution. The reaction was concentrated togive a light solid. The solid was purified by prep-HPLC (Column:Phenomenex Gemini 150*25 mm*10 um; Conditions: water (0.05% HCl)-ACN;Gradient 60%-100% B; Gradient Time (min): 10) to afford Compound 43 (30mg, 27%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 6.95-6.86 (m, 2H), 6.58-6.47 (m, 2H),4.05-3.95 (m, 2H), 2.97 (s, 3H), 2.60-2.52 (m, 1H), 2.18-2.07 (m, 1H),1.96-1.51 (m, 9H), 1.51-1.02 (m, 17H), 0.66 (s, 3H).

LCMS Rt=0.971 min in 1.5 min chromatography, 5-95 AB, purity 100%, MSESI calcd. for C₂₁H₄₁FNO₂ [M+H]⁺ 442, found 442.

Example 43. Synthesis of Compound 44

The synthesis of C1 is disclosed in WO2015/180679.

Step 1 (C2). Liquid bromine (6.55 g, 41.0 mmol) was added slowly to avigorously stirred sodium hydroxide aqueous solution (54.6 mL, 3 M, 164mmol) at 0° C. When all the bromine was dissolved, the mixture wasdiluted with cold dioxane (15 mL) and added slowly to a stirred solutionof C1 (5 g, 13.7 mmol) in dioxane (20 mL) and water (15 mL). Thehomogeneous yellow solution became colorless slowly and a whiteprecipitate formed, and the reaction mixture was stirred at 25° C. for 5hrs. The remaining oxidizing reagent was quenched by addition of anaqueous Na₂S₂O₃ solution (30 mL) and the mixture was then heated to 80°C. until the solid material dissolved. The solution was acidified withHCl (3 M, 40 mL), and a solid precipitated. The solid was filtered andwashed with water (3×100 mL) to give a solid, which was dried in vacuoto afford C₂ (5 g, crude) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 11.89 (br s, 1H), 4.13 (br s, 1H), 3.46 (q,J=7.0 Hz, 2H), 3.32-3.26 (m, 2H), 2.29 (t, J=9.2 Hz, 1H), 1.99-1.89 (m,2H), 1.78-1.46 (m, 7H), 1.41-1.14 (m, 11H), 1.11 (t, J=7.0 Hz, 3H),1.07-0.91 (m, 3H), 0.62 (s, 3H).

Step 2 (Compound 44). To a solution of C2 (100 mg, 0.274 mmol) in DCM (3mL) was added HATU (156 mg, 0.411 mmol) and Et₃N (137 mg, 1.36 mmol) at25° C. The reaction mixture was stirred at 25° C. for 0.5 hour.1,2,3,4-Tetrahydroisoquinoline (54.7 mg, 0.411 mmol) was added to thereaction mixture at 25° C. The reaction mixture was stirred at 25° C.for 1 hour. The reaction mixture was quenched with ice-water (10 mL).The aqueous phase was extracted with EtOAc (3×20 mL). The combinedorganic phase was washed with brine (2×10 mL), dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by HPLC(Instrument: BQ; Method: Column YMC-Actus Triart C18 100*30 mm*5 um;Conditions: water(0.05% HCl)-ACN; Begin B: 80 End B: 100; Gradient Time(min): 8; 100% B Hold Time (min): 2; FlowRate(ml/min); 25; Injections:8) to obtain Compound 44 (65.0 mg, 50%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.26-7.02 (m, 4H), 4.88-4.65 (m, 2H),4.00-3.65 (m, 2H), 3.56-3.36 (m, 4H), 2.90-2.66 (m, 3H), 2.35 (m, 1H),1.80-1.56 (m, 9H), 1.56-0.96 (m, 17H), 0.76-0.72 (m, 3H).

LCMS Rt=0.971 min in 1.5 min chromatography, 5-95 AB, purity 100%, MSESI calcd. for C₃₁H₄₆NO₃ [M+H]⁺ 480, found 480.

Example 44. Synthesis of Compound 45 and Compound 46

Step 1 (D2). To a solution of commercially available D1 (10 g, 46.6mmol) in THF (60 mL) was added Lawesson's reagent (9.42 g, 23.3 mmol).The mixture was stirred at 20° C. for 1 h. The mixture was concentratedin vacuo. To the residue was added NaHCO₃ (120 mL, sat.) and the mixturewas stirred at 20° C. for 1 h. The mixture was filtered, the precipitatewas washed with water (2×50 mL), dried in vacuo to give D2 (9.5 g, 89%)as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.49 (br, 2H), 4.65 (dd, J=3.6, 8.4 Hz, 1H),3.70-3.30 (m, 2H), 2.70-1.80 (m, 4H), 1.46 (s, 9H).

LCMS Rt=0.814 min in 2.0 min chromatography, 10-80, purity 100%, MS ESIcalcd. for C₅H₁₁N₂S [M+H-Me₂C═CH₂—CO₂]⁺ 131, found 131.

Step 2 (D3). To a solution of D2 (5 g, 21.7 mmol) in DME (250 mL) wasadded KHCO₃ (17.3 g, 173 mmol) and bromoacetone (8.91 g, 65.1 mmol). Themixture was stirred at 20° C. for 1 h. To the mixture was added pyridine(14.5 g, 184 mmol) and TFAA (18.2 g, 86.8 mmol) at 0° C. The mixture wasstirred at 20° C. for 16 h. To the mixture was added NaHCO₃ (150 mL,sat.) and the mixture was concentrated in vacuo. The residue wasdissolved in EtOAc (200 mL) and washed with water (200 mL), dried overNa₂SO₄, filtered, concentrated in vacuo and purified by flash column(0˜20% EtOAc in PE) to give D3 (3.6 g, 62%) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 6.73 (s, 1H), 5.38-5.00 (m, 1H), 3.69-3.37 (m,2H), 2.41 (s, 3H), 2.38-2.11 (m, 2H), 2.00-1.82 (m, 2H), 1.54-1.29 (m,9H).

LCMS Rt=1.059 min in 2.0 min chromatography, 10-80, purity 97.4% (220n), MS ESI calcd. for C₁₃H₂₁N₂O₂S [M+H]⁺ 269, found 269.

Step 3 (D4). To D3 (3.6 g, 13.4 mmol) was added HCl/dioxane (20 mL, 4M). The mixture was stirred at 20° C. for 15 min. The mixture wasconcentrated in vacuo. The residue was dissolved in water (25 mL) andwashed with MTBE (20 mL). The aqueous phase was basified with Na₂CO₃(sat.) till pH=10. The mixture was extracted with MTBE (2×20 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, concentratedin vacuo to give 5-methyl-2-(pyrrolidin-2-yl)thiazole, D4 (1 g, purity90%, yield 40%) as a light brown oil.

¹H NMR (400 MHz, CDCl₃) δ 6.73 (s, 1H), 4.52 (dd, J=6.4 Hz, 8.0 Hz, 1H),3.18-3.10 (m, 1H), 3.10-3.00 (m, 1H), 2.40 (s, 3H), 2.34-2.22 (m, 1H),2.21-2.04 (br, 1H), 2.00-1.75 (m, 5H).

LCMS Rt=0.544 min in 2.0 min chromatography, 0-30 AB, purity 100%, MSESI calcd. for C₈H₁₃N₂S [M+H]⁺ 169, found 169.

Step 4 (Mixture of Compound 45 and Compound 46). To a solution of C2(200 mg, 0.548 mmol) in DCM (5 mL) was added HATU (312 mg, 0.822 mmol)and Et₃N (275 mg, 2.73 mmol) at 25° C. The reaction mixture was stirredat 25° C. for 0.5 hour. 5-methyl-2-(pyrrolidin-2-yl)thiazole (D4, 138mg, 0.822 mmol) was added to the reaction mixture at 25° C. Afterstirring at 25° C. for 10 hours, the reaction mixture was quenched withice-water (20 mL) and extracted with DCM (3×5 mL). The combined organicphase was dried over anhydrous Na₂SO₄, filtered, concentrated to give aracemic mixture of Compound 45 and Compound 46 (200 mg) as an oil thatwas further purified.

LCMS Rt=0.902 min in 1.5 min chromatography, 5-95AB, purity 65%, MS ESIcalcd. for C₃₀H₄₇N₂O₃S [M+H]⁺ 515, found 515.

Step 5 (Compound 45 and Compound 46). The impure racemic mixture ofCompound 45 and Compound 46 (200 mg, 0.388 mmol) was separated by SFC(column: AD (250 mm*30 mm, 5 um), gradient: 45-45% B (A=0.05% NH₃/H₂O,B=MeOH), flow rate: 60 mL/min) to give Compound 45 (Peak 1, 33 mg, 16%)and Compound 46 (Peak 2, 43 mg, 21%) as a solid.

SFC Peak 1: Rt=5.407 min and Peak 2 Rt=7.126 min in 10 minchromatography, AD_3_IPA_DEA_5_40_25ML. (Column: Chiralpak AD-3 150×4.6mm I.D., 3 um Mobile phase: A: CO₂ B:iso-propanol (0.05% DEA) Gradient:from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for2.5 min Flow rate: 2.5 mL/min Column temp.: 35° C.).

Compound 45

¹H NMR (400 MHz, CDCl₃) δ 6.83-6.67 (m, 1H), 5.49-5.22 (m, 1H),3.79-3.59 (m, 2H), 3.56-3.37 (m, 4H), 2.75-2.68 (m, 1H), 2.60-2.53 (m,1H), 2.50-2.37 (m, 3H), 2.32-1.90 (m, 6H), 1.88-1.65 (m, 7H), 1.49-1.25(m, 9H), 1.22-1.19 (m, 3H), 1.18-0.99 (m, 4H), 0.98-0.93 (m, 1H), 0.83(s, 3H).

LCMS Rt=1.261 min in 2.0 min chromatography, 10-80AB, purity 100%, MSESI calcd. for C₃₀H₄₇N₂O₃S [M+H]⁺ 515, found 515.

SFC Rt=5.390 min in 10 min chromatography, AD_3_EtOH_DEA_5_40_25ML, 100%de. (Column: Chiralpak AD-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂B:iso-propanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min andhold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/minColumn temp.: 35° C.).

Compound 46

¹H NMR (400 MHz, CDCl₃) δ 6.80-6.64 (m, 1H), 5.60-5.35 (m, 1H),3.86-3.73 (m, 1H), 3.64-3.34 (m, 5H), 2.85-2.55 (m, 2H), 2.49-2.36 (m,3H), 2.33-2.15 (m, 3H), 2.08-1.94 (m, 2H), 1.89-1.58 (m, 8H), 1.51-1.33(m, 7H), 1.32-1.02 (m, 10H), 0.74 (s, 3H).

LCMS Rt=1.271 min in 2.0 min chromatography, 10-80AB, purity 100%, MSESI calcd. for C₃₀H₄₇N₂O₃S [M+H]⁺ 515, found 515.

SFC Rt=7.166 min in 10 min chromatography, AD_3_EtOH_DEA_5_40_25ML,99.8% de. (Column: Chiralpak AD-3 150×4.6 mm I.D., 3 um Mobile phase: A:CO₂ B:iso-propanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 minand hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/minColumn temp.: 35° C.).

Example 45. Synthesis of Compound 47

To a solution of C2 (200 mg, 0.548 mmol) in DMF (5 mL) was added HATU(312 mg, 0.822 mmol) and Et₃N (275 mg, 2.73 mmol) at 25° C. The reactionmixture was stirred at 25° C. for 0.5 hour. 4-fluoro-2,6-dimethylaniline(114 mg, 0.822 mmol) was added to the reaction mixture at 25° C. Afterstirring at 50° C. for 10 hours, the reaction mixture was quenched withwater (20 mL) and extracted with EtOAc (3×10 mL). The combined organicphase was washed with 3% aqueous LiCl (2×20 mL), dried over anhydrousNa₂SO₄, filtered, concentrated and purified by flash silica gelchromatography (0-40% of EtOAc in PE) to give 50 mg impure product,which was purified by prep-HPLC (column: YMC-Actus Triart C18 100*30mm*5 um), gradient: 80-100% B (A=water (0.05% HCl), B=MeCN), flow rate:25 mL/min) to give Compound 47 (12 mg, 24%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 6.82-6.72 (m, 2H), 6.58-6.48 (m, 1H),3.61-3.33 (m, 4H), 2.88-2.59 (m, 1H), 2.39-2.31 (m, 1H), 2.20 (s, 6H),2.13-2.05 (m, 1H), 1.94-1.58 (m, 9H), 1.52-1.35 (m, 7H), 1.30-1.06 (m,9H), 0.81 (s, 3H).

LCMS Rt=1.313 min in 2.0 min chromatography, 10-80AB, purity 100%, MSESI calcd. for C₃₀H₄₅FNO₃ [M+H]⁺ 486, found 486.

Example 46. Synthesis of Compound 48 and Compound 49

Step 1 (Compound 48). To a solution of C2 (200 mg, 0.548 mmol) in DCM (5mL) was added HATU (312 mg, 0.822 mmol) and Et₃N (275 mg, 2.73 mmol) at25° C. The reaction mixture was stirred at 25° C. for 0.5 hour.(R)-4-(1-aminoethyl)benzonitrile (120 mg, 0.822 mmol) was added to thereaction mixture at 25° C. After stirring at 25° C. for 10 hours, thereaction mixture was quenched with water (20 mL) and extracted withEtOAc (3×5 mL). The combined organic phase was washed with saturatedbrine (2×10 mL), dried over anhydrous Na₂SO₄, filtered and concentratedto give a residue, which was purified by flash silica gel chromatography(0-60% of EtOAc in PE) and prep-TLC (PE:EtOAc=1:1) to give Compound 48(150 mg, 55%) as a solid.

¹H NMR (400 MHz, CDCl₃) 7.65-7.59 (m, 2H), 7.44-7.37 (m, 2H), 5.52-5.44(m, 1H), 5.22-5.11 (m, 1H), 3.57-3.49 (m, 2H), 3.48-3.38 (m, 2H), 2.74(s, 1H), 2.21-2.07 (m, 2H), 1.95-1.88 (m, 1H), 1.87-1.62 (m, 7H),1.51-1.32 (m, 9H), 1.32-1.24 (m, 3H), 1.23-1.18 (m, 4H), 1.17-1.02 (m,4H), 0.68 (s, 3H).

LCMS Rt=4.765 min in 7.0 min chromatography, 10-80AB, purity 100%, MSESI calcd. for C₃₁H₄₅N₂O₃ [M+H]⁺ 493, found 493.

Step 2 (E1). To a solution of Compound 48 (120 mg, 0.275 mmol) in DCM (3mL) was added imidazole (198 mg, 2.91 mmol) and TMSCl (236 mg, 2.18mmol) at 20° C. After stirring at 20° C. for 30 minutes, the mixture wasquenched with water (10 mL) and extracted with DCM (2×5 mL). Thecombined organic layers were washed with water (10 mL), dried overNa₂SO₄, filtered and concentrated in vacuo to give E1 (137 mg, crude) asa solid.

¹H NMR (400 MHz, CDCl₃) δ 7.65-7.59 (m, 2H), 7.44-7.37 (m, 2H),5.52-5.44 (m, 1H), 5.22-5.11 (m, 1H), 3.54-3.32 (m, 4H), 2.22-2.09 (m,2H), 1.97-1.88 (m, 1H), 1.81-1.65 (m, 7H), 1.52-1.41 (m, 6H), 1.38-1.16(m, 11H), 1.10-0.97 (m, 3H), 0.69 (s, 3H), 0.11 (s, 9H).

Step 3 (E2). To a solution of E1 (137 mg, 0.242 mmol) in DMF (3 mL) wasadded NaH (96.6 mg, 2.42 mmol, 60% purity) at 0° C. After stirring at 0°C. under N₂ for 10 minutes, MeI (515 mg, 3.63 mmol) was slowly added at0° C. under N₂. After stirring at this temperature for 10 minutes, thereaction mixture was quenched with water (10 mL) and extracted withEtOAc (2×5 mL). The combined organic phase was washed with LiCl (10 mL,3% aqueous), dried over Na₂SO₄, filtered and concentrated to give E2(140 mg, crude) as a brown oil.

¹H NMR (400 MHz, CDCl₃) δ 7.71-7.57 (m, 2H), 7.41-7.34 (m, 2H),6.21-6.12 (m, 0.84H), 5.41-5.28 (m, 0.16H), 3.55-3.31 (m, 4H), 2.78-2.62(m, 4H), 2.37-2.25 (m, 1H), 1.82-1.65 (m, 9H), 1.53-1.39 (m, 8H),1.36-1.29 (m, 5H), 1.15-1.04 (m, 6H), 0.91-0.75 (m, 3H), 0.10 (s, 9H).

Step 4 (Compound 49). A solution of E2 (140 mg, 0.241 mmol) in TBAF (2.4mL, 2.4 mmol, 1M in THF) was heated at 30° C. for 30 minutes. Themixture was quenched with 50% NH₄Cl (10 mL) and extracted with EtOAc(2×5 mL). The combined organic phase was washed with brine (2×10 mL),dried over Na₂SO₄, filtered, concentrated and purified by flash silicagel chromatography (0-15% of EtOAc in PE) to give Compound 49 (18 mg,15%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.71-7.57 (m, 2H), 7.41-7.34 (m, 2H),6.21-6.12 (m, 0.84H), 5.41-5.28 (m, 0.16H), 3.59-3.33 (m, 4H), 2.79-2.56(m, 5H), 2.36-2.21 (m, 1H), 1.85-1.61 (m, 8H), 1.52-1.33 (m, 10H),1.32-1.23 (m, 3H), 1.22-1.17 (m, 4H), 1.16-1.06 (m, 3H), 0.91-0.75 (m,3H).

LCMS Rt=1.126 min in 2.0 min chromatography, 30-90AB, purity 100%, MSESI calcd. for C₃₂H₄₇N₂O₃ [M+H]⁺ 507, found 507.

Example 47. Synthesis of Compound 50

ep 1 (Compound 50). To a solution of C2 (100 mg, 0.274 mmol) in DCM (3mL) was added HATU (156 mg, 0.411 mmol) and TEA (137 mg, 1.36 mmol) at25° C. After stirring at 25° C. for 10 min, piperidine (34.9 mg, 0.411mmol) was added to the reaction mixture at 25° C. The reaction mixturewas stirred at 25° C. for 1 hour and quenched with ice-water (10 mL).The aqueous phase was extracted with EtOAc (3×20 mL). The combinedorganic phase was washed with brine (2×10 mL), dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by HPLC(Instrument: BQ; Method: Column YMC-Actus Triart C18 100*30 mm*5 um;Conditions: water(0.05% HCl)-ACN; Begin B: 80; End B: 100; Gradient Time(min): 8; 100% B Hold Time (min): 2; FlowRate(ml/min): 25; Injections:7) to obtain Compound 50 (78 mg, 66%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 3.65-3.38 (m, 8H), 2.75-2.65 (m, 2H),2.38-2.25 (m, 1H), 1.86-1.56 (m, 12H), 1.50-1.00 (m, 19H), 0.72 (s, 3H).

LCMS Rt=1.104 min in 2 min chromatography, 30-90 AB, purity 100%, MS ESIcalcd. for C₂₇H₄₆NO₃ [M+H]⁺ 432, found 432.

Example 48. Synthesis of Compound 51

Step 1 (Compound 51). To a solution of C2 (100 mg, 0.274 mmol) and4-fluoro-2-methylaniline (41.0 mg, 0.328 mmol) in DCM (3 mL) was addedEDCI (78.7 mg, 0.411 mmol) and DMAP (16.7 mg, 0.137 mmol). The mixturewas stirred at 30° C. for 3 hrs. The reaction mixture was quenched withwater (5 mL) and extracted with DCM (2×5 mL). The combined organiclayers were washed with brine (5 mL), dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by HPLC(Column: Xtimate C18 150*25 mm*5 um; Condition: water (0.05% HCl)-ACN;Gradient: 60%˜90% B; FlowRate: 30 mL/min) to give Compound 51 (23 mg,18%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.78-7.72 (m, 1H), 6.92-6.85 (m, 2H), 6.72 (s,1H), 3.58-3.50 (m, 2H), 3.48-3.38 (m, 2H), 2.35-2.21 (m, 5H), 2.09-2.02(m, 1H), 1.88-1.71 (m, 6H), 1.69-1.62 (m, 2H), 1.52-1.34 (m, 8H),1.31-1.09 (m, 9H), 0.77 (s, 3H).

LCMS Rt=1.123 min in 2.0 min chromatography, 30-90AB, purity 100%(HPLC), MS ESI calcd. for C₂₉H₄₃FNO₃ [M+H]⁺ 472, found 472.

Example 49. Synthesis of Compound 52

Step 1 (C₃). To a solution of C2 (1 g, 2.74 mmol) in toluene (20 mL) wasadded 1,2-di(pyridin-2-yl)disulfane (1.2 g, 5.48 mmol) andtriphenylphosphine (1.43 g, 5.48 mmol). The mixture was stirred at 25°C. for 16 hrs. The reaction mixture was purified by a silica gelchromatography (PE/EtOAc=5/1) to give C₃ (800 mg, 64%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.62-8.61 (m, 1H), 7.74-7.70 (m, 1H), 7.60 (d,J=8 Hz, 1H), 7.28-7.27 (m, 1H), 3.53 (q, J=7 Hz, 2H), 3.43 (q, J=9.3 Hz,2H), 2.79-2.68 (m, 2H), 2.28-2.16 (m, 2H), 1.94-1.60 (m, 8H), 1.50-1.33(m, 7H), 1.30-1.03 (m, 9H), 0.74 (s, 3H).

Step 2 (Compound 52). To a solution of C2 (100 mg, 0.218 mmol) in DCM (3mL) was added AgOTf (56 mg, 0.218 mmol), followed by1,2,3,4-tetrahydroquinoline (43.5 mg, 0.327 mmol) at 25° C. Afterstirring the reaction at 25° C. for 1 hrs, the reaction mixture wasfiltered and the filter cake was washed with DCM (15 mL). The combinedorganic layers were washed with 1M HCl (10 mL), brine (50 mL), driedover Na₂SO₄, filtered and concentrated in vacuo to give an oil (95 mg)which was purified by HPLC (Column: YMC-Actus Triart C18 100*30 mm*5 um;Conditions: water(0.05% HCl)-ACN; Gradient: 85% B˜100% B; FlowRate: 25mL/min) to give Compound 52 (16 mg, 17%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.23-7.02 (m, 4H), 4.42-4.22 (m, 1H),3.54-3.48 (m, 2H), 3.43-3.34 (m, 2H), 3.32-3.12 (m, 2H), 2.79-2.59 (m,3H), 2.34-2.20 (m, 1H), 2.13-2.03 (m, 1H), 1.82-1.63 (m, 6H), 1.52-1.35(m, 6H), 1.34-1.24 (m, 4H), 1.22-1.14 (m, 5H), 1.10-0.83 (m, 5H), 0.73(s, 3H).

LCMS Rt=1.190 min in 2.0 min chromatography, 30-90AB, purity 100%, MSESI calcd. for C₃₁H₄₆NO₃ [M+H]⁺ 480, found 480.

Example 50. Synthesis of Compound 53

Step 1 (Compound 53). To a solution of C3 (100 mg, 0.218 mmol) in DCM (3mL) was added AgOTf (56 mg, 0.218 mmol), followed by2-amino-5-fluorobenzonitrile (44.5 mg, 0.327 mmol) at 25° C. Afterstirring the reaction at 25° C. for 1 hrs, the reaction mixture wasfiltered and the filter cake was washed with DCM (15 mL). The combinedorganic layers were washed with 1M HCl (10 mL), brine (50 mL), driedover Na₂SO₄, filtered and concentrated in vacuo to give an oil (90 mg)which was purified by HPLC (Column: YMC-Actus Triart C18 100*30 mm*5 um;Conditions: water(0.05% HCl)-ACN; Gradient: 75% B˜100% B; FlowRate: 25mL/min) to give Compound 53 (18 mg, 20%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.46-8.40 (m, 1H), 7.45 (s, 1H), 7.34-7.26 (m,2H), 3.57-3.50 (m, 2H), 3.48-3.38 (m, 2H), 2.71 (s, 1H), 2.43-2.36 (m,1H), 2.33-2.21 (m, 1H), 2.16-2.09 (m, 1H), 1.92-1.72 (m, 6H), 1.66-1.59(m, 2H), 1.52-1.38 (m, 7H), 1.34-1.25 (m, 3H), 1.24-1.17 (m, 4H),1.16-1.07 (m, 2H), 0.75 (s, 3H).

¹⁹F NMR (400 MHz, CDCl₃) δ −116.43 (s).

LCMS Rt=1.094 min in 2.0 min chromatography, 30-90AB, purity 100%, MSESI calcd. for C₂₉H₄₀FN₂O₃[M+H]⁺ 483, found 483.

Example 51. Synthesis of Compound 54

Step 1 (Compound 54). To a solution of C3 (100 mg, 0.218 mmol) in DCM (3mL) was added AgOTf (56 mg, 0.218 mmol), followed by4-amino-3-methylbenzonitrile (43.2 mg, 0.327 mmol) at 25° C. Afterstirring the reaction at 25° C. for 1 hr, the reaction mixture wasfiltered and the filter cake was washed with DCM (15 mL). The combinedorganic layers were washed with 1M HCl (10 mL), brine (50 mL), driedover Na₂SO₄, filtered and concentrated in vacuo to give an oil (93 mg)which was purified by HPLC (Column: YMC-Actus Triart C18 100*30 mm*5 um;Conditions: water(0.05% HCl)-ACN; Gradient: 75% B˜100% B; FlowRate: 25mL/min) to give Compound 54 (12 mg, 13%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, J=8.4 Hz, 1H), 7.53-7.48 (m, 1H),7.46 (s, 1H), 6.96 (s, 1H), 3.57-3.50 (m, 2H), 3.47-3.38 (m, 2H), 2.75(s, 1H), 2.40-2.24 (m, 5H), 2.06-1.99 (m, 1H), 1.91-1.72 (m, 6H),1.68-1.60 (m, 2H), 1.50-1.36 (m, 7H), 1.32-1.18 (m, 6H), 1.18-1.04 (m,3H), 0.75 (s, 2H), 0.77-0.72 (m, 1H).

LCMS Rt=1.129 min in 2.0 min chromatography, 30-90AB, purity 100%, MSESI calcd. for C₃₀H₄₃N₂O₃ [M+H]⁺ 479, found 479.

Example 52. Synthesis of Compound 55

Step 1 (F2). To a solution of commercially available F1 (20 g, 80.2mmol) in DCM (200 mL) was added 2,2-dimethoxyethanamine (8.43 g, 80.2mmol), HOBt (14 g, 104 mmol), EDCI (19.9 g, 104 mmol) and TEA (40.5 g,401 mmol) at 25° C. The mixture was stirred at 25° C. for 19 hours. Themixture was filtered. The filtrate was washed with water (2×150 mL),brine (2×150 mL), dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo to give F2 (27 g, crude) as an oil.

Step 2 (F3) To a solution of F2 (17 g, 50.5 mmol) in acetone (200 mL)was added aqueous HCl (151 mL, 3M) at 25° C. The mixture was stirred at25° C. for 16 hours. The mixture was extracted with EtOAc (3×250 mL).The organic phase was washed with water (3×600 mL), sat. NaHCO₃ (3×500mL), brine (3×450 mL), dried over Na₂SO₄, filtered, concentrated invacuo to give F3 (5.57 g) as an oil.

Step 3 (F4). To a stirred solution of F3 (5.57 g, 19.1 mmol) andperchloroethane (9.04 g, 38.2 mmol) in dichloromethane (200 mL) wasadded PPh₃ (10 g, 38.2 mmol). The mixture was stirred at 0° C. for 15min, Et₃N (5.51 mL, 38.2 mmol) was then added and the mixture wasstirred at 25° C. for 18 hrs. The mixture was washed with water (2×150mL), brine (2×150 mL), dried over Na₂SO₄, filtered, concentrated invacuo to give a crude product, which was purified by flash silica gelchromatography (0-65% EtOAc in PE) to give F4 (2.7 g, 52%) as a whiteyellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.75-7.45 (s, 1H), 7.10-6.98 (m, 2H),5.20-4.95 (m, 3H), 3.75-3.45 (m, 2H), 2.40-2.20 (m, 3H), 2.00-1.95 (m,1H)

Step 4 (F5). To a solution of F4 (1.3 g, 4.77 mmol) in AcOH (5 mL) wasadded HBr (10 mL, 35% in AcOH) at 25° C. The mixture was stirred at 25°C. for 4 hours. MTBE (25 mL) was added and solid was produced. Themixture was filtered. The filtered cake was washed with MTBE (15 mL) anddried in vacuo at 50° C. to give F5 (800 mg, 77%) as a solid.

¹H NMR (400 MHz, methanol-d₄) δ 8.03 (s, 1H), 7.27 (s, 1H), 5.05-4.80(m, 1H), 3.60-3.45 (m, 2H), 2.60-2.55 (m, 1H), 2.45-2.35 (m, 1H),2.31-2.20 (m, 2H)

Step 5 (Compound 55). To a solution of C2 (200 mg, 0.548 mmol) in DCM (5mL) was added HATU (312 mg, 0.822 mmol) and Et₃N (276 mg, 2.73 mmol) at25° C. The reaction mixture was stirred at 25° C. for 0.5 hour.(S)-2-(pyrrolidin-2-yl)oxazole hydrobromide (180 mg, 0.822 mmmol) wasadded to the reaction mixture at 25° C. for 18 hours. The reactionmixture was diluted with EtOAc (30 mL) and washed with water (50 mL),brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated togive the crude. The crude was purified by silica gel chromatography withPE/EtOAc=0/1-1/1 to give Compound 55 (200 mg,) as a light solid.Compound 55 was further purified by pre-HPLC (Conditions: water (0.05%ammonia hydroxide v/v)-ACN, Column: Phenomenex Gemini C18 250*50 mm*10um, Gradient Time: 8 min) to give Compound 55 (100 mg, 50%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.62-7.50 (m, 1H), 7.14-6.99 (m, 1H),5.27-5.11 (m, 1H), 3.93-3.29 (m, 7H), 2.77-2.49 (m, 2H), 2.31-1.99 (m,5H), 1.84-1.60 (m, 8H), 1.49-1.32 (m, 7H), 1.25-1.17 (m, 6H), 1.16-1.03(m, 3H), 0.85-0.76 (m, 3H)

LCMS Rt=0.977 min in 2.0 min chromatography, 30-90AB, purity 100%; MSESI calcd. for C₂₉H₄₅N₂O₄ [M+H]⁺ 485, found 485.

SFC Rt=1.488 min in 3.0 min chromatography, AD-H_3UM_4_5_40_4ML_3MIN.M,100% de. (Column: Chiralpak AD-3 50*4.6 mm I.D., 3 um; Mobile phase:A:CO₂ B:iso-propanol (0.05% DEA); Gradient: hold 5% for 0.2 min, thenfrom 5% to 40% of B in 1.4 min and hold 40% for 1.05 min, then 5% of Bfor 0.35 min; Flow rate: 4 mL/min Column temp: 40° C.).

Example 53. Synthesis of Compound 56 and Compound 57

Step 1 (G2). To a solution of titanium(IV) isopropoxide (2.51 g, 8.67mmol) in methanamine (611 mg, 2M in MeOH) was added commerciallyavailable 1-(4-fluorophenyl)propan-1-one (G1, 1 g, 6.57 mmol) at 25° C.The mixture was stirred at 25° C. for 12 hours. To the mixture was addedNaBH₄ (248 mg, 6.57 mmol). The mixture was stirred at 25° C. for 10 min.The mixture was poured into saturated NH₄Cl (10 mL) and water (10 mL).The reaction mixture was filtered and washed with PE (3×10 mL). Thefiltrate was concentrated to give G2 (400 mg, 36%) as an oil, which wasused in next step without further purification.

Step 2 (Mixture of Compound 56 and 57). To a solution of C2 (200 mg,0.548 mmol) in DCM (5 mL) was added HATU (312 mg, 0.822 mmol) and Et₃N(276 mg, 2.73 mmol) at 25° C. After stirring at 25° C. for 0.5 hour,1-(4-fluorophenyl)-N-methylpropan-1-amine (G2, 137 mg, 0.822 mmol) wasadded to the reaction mixture at 25° C. The reaction mixture was stirredat 40° C. for 10 hours. The residue was quenched with ice-water (10 mL).The aqueous phase was extracted with EtOAc (3×20 mL). The combinedorganic phase was washed with saturated brine (2×10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give a mixture ofCompound 56 and 57 (300 mg, crude) as a solid, which was furtherpurified as described in step 3 below.

Step 3 (Compound 56 and Compound 57). A mixture of Compound 56 and 57(300 mg, crude) was purified by silica gel chromatography eluted withPE:EtOAc=3/1 to give Compound 56 (35 mg, 12%) as a solid and Compound 57(46 mg, 15%) as a solid.

Compound 56

¹H NMR (400 MHz, CDCl₃) δ 7.28-7.21 (m, 2H), 7.08-6.94 (m, 2H),5.97-5.85 (m, 0.9H), 5.08-4.99 (m, 0.1H), 3.57-3.49 (m, 2H), 3.47-3.36(m, 2H), 2.74-2.64 (m, 4H), 2.39-2.25 (m, 1H), 2.01-1.90 (m, 1H),1.88-1.60 (m, 10H), 1.51-1.05 (m, 17H), 0.96 (t, J=7.28, 3H), 0.94 (s,0.4H), 0.80 (s, 2.6H).

LCMS Rt=5.531 min in 7 min chromatography, 10-80AB, purity 98%, MS ESIcalcd. for C₃₂H₄₉FNO₃ [M+H]⁺ 514, found 514.

SFC Rt=4.251 min in 10 min chromatography, OD_3_EtOH_DEA_5_40_25ML, 98%de. (Column: Chiralcel OD-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Columntemp.: 35° C.).

Compound 57

¹H NMR (400 MHz, CDCl₃) δ 7.29-7.23 (m, 2H), 7.19-7.15 (m, 0.2H),7.08-6.96 (m, 1.8H), 5.94-5.75 (m, 0.9H), 5.02-4.94 (m, 0.1H), 3.57-3.48(m, 2H), 3.47-3.36 (m, 2H), 2.79-2.64 (m, 5H), 2.36-2.10 (m, 1H),2.03-1.96 (m, 1H), 1.86-1.61 (m, 8H), 1.50-0.97 (m, 18H), 0.95-0.88 (m,3H), 0.87 (s, 0.4H), 0.80 (s, 2.6H).

LCMS Rt=5.485 min in 7 min chromatography, 10-80AB, purity 98%, MS ESIcalcd. for C₃₂H₄₉FNO₃ [M+H]⁺ 514, found 514.

SFC Rt=2.890 min in 10 min chromatography, OD_3_EtOH_DEA_5_40_25ML, 99%de. (Column: Chiralcel OD-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Columntemp.: 35° C.).

Example 54. Synthesis of Compound 58 and Compound 59

Step 1 (H2). To a solution of commercially available H1 (3 g, 19.7 mmol)in MeOH (100 mL) was added AcONH₄ (15.1 g, 196 mmol) and NaBH₃CN (6.18g, 98.4 mmol) at 20° C. The mixture was stirred at 20° C. for 19 hours.Water (100 mL) was added and a solid was produced. The mixture wasfiltered. The filtrate was extracted with EtOAc (2×80 mL). The combinedorganic phase was washed with water (2×100 mL), brine (2×80 mL), driedover Na₂SO₄, filtered, concentrated in vacuo to give H2 (2.15 g, 71%) asa white yellow oil, which was used in next step without furtherpurification.

Step 2 (Compound 58 and Compound 59). To a solution of C2 (200 mg, 0.548mmol) in DCM (5 mL) was added HATU (312 mg, 0.822 mmol) and TEA (276 mg,2.73 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 0.5hour. 1-(4-fluorophenyl) propan-1-amine H2 (125 mg, 0.822 mmol) wasadded to the reaction mixture at 25° C. The reaction mixture was stirredat 40° C. for 10 hours. The residue was quenched with ice-water (10 mL).The aqueous phase was extracted with EtOAc (3×20 mL). The combinedorganic phase was washed with saturated brine (2×10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified bysilica gel chromatography eluted with PE:EtOAc=3/1 to give Compound 58(100 mg, 37%, Rf=0.6 in PE/EtOAc=3/1) as a solid and Compound 59 (100mg, 37% Rf=0.5 in PE/EtOAc=3/1) as a solid.

Compound 58 (100 mg) was further purified twice by silica gelchromatography and then by SFC (Column: Chiralcel OJ-3 150×4.6 mm I.D.,3 um Mobile phase: A: CO₂ B:ethanol (0.05% DEA) Gradient: from 5% to 40%of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flowrate: 2.5 mL/min Column temp.: 35° C.) to give Compound 58 (23 mg,yield) as a solid.

Compound 59 (100 mg) was purified by SFC twice (Column: Chiralcel OJ-3150×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B:ethanol (0.05% DEA)Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5%of B for 2.5 min Flow rate: 2.5 mL/min Column temp.: 35° C.) to affordCompound 59 (17 mg, yield) as a solid.

Compound 58

¹H NMR (400 MHz, CDCl₃) δ 7.26-7.21 (m, 2H), 7.05-6.98 (m, 2H),5.46-5.40 (m, 1H), 4.88 (q, J=7.53 Hz, 1H), 3.53 (q, J=7.03 Hz, 2H),3.43 (q, J=9.54, 2H), 2.73 (s, 1H), 2.22-2.03 (m, 2H), 1.99-1.92 (m,1H), 1.87-1.61 (m, 9H), 1.51-1.02 (m, 17H), 0.89 (t, J=7.53, 3H), 0.70(s, 3H).

LCMS Rt=1.334 min in 2.0 min chromatography, 10-80AB, purity 100%, MSESI calcd. for C₃₁H₄₇FNO₃ [M+H]⁺ 500, found 500.

SFC Rt=2.890 min in 10 min chromatography, OJ_3_EtOH_DEA_5_40_25ML, 98%de. (Column: Chiralcel OJ-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Columntemp.: 35° C.).

Compound 59

¹H NMR (400 MHz, CDCl₃) δ 7.25-7.21 (m, 2H), 7.04-6.96 (m, 2H),5.49-5.40 (m, 1H), 4.85 (q, J=7.36 Hz, 1H), 3.53 (q, J=6.86 Hz, 2H),3.42 (q, J=9.12 Hz, 2H), 2.72 (s, 1H), 2.22-2.07 (m, 2H), 1.86-1.70 (m,7H), 1.68-1.62 (m, 2H), 1.49-0.95 (m, 18H), 0.88 (t, J=7.4 Hz, 3H), 0.49(s, 3H).

LCMS Rt=1.322 min in 2.0 min chromatography, 10-80AB, purity 100%, MSESI calcd. for C₃₁H₄₇FNO₃ [M+H]⁺ 500, found 500.

SFC Rt=2.668 min in 10 min chromatography, OJ_3_EtOH_DEA_5_40_25ML, 95%de. (Column: Chiralcel OJ-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Columntemp.: 35° C.).

Example 55. Synthesis of Compound 60

Step 1 (I2). To a solution of commercially available I1 (20 g, 80.2mmol) in DCM (200 mL) was added 2, 2-dimethoxyethanamine (8.43 g, 80.2mmol), HOBt (14 g, 104 mmol), EDCI (19.9 g, 104 mmol) and TEA (40.5 g,401 mmol) at 25° C. The mixture was stirred at 25° C. for 19 hours. Themixture was filtered, concentrated in vacuo to give a crude product,which was purified by flash silica gel chromatography (0-70% EtOAc inPE) to give 12 (20 g, 74%) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 7.32 (s, 5H), 5.20-5.00 (m, 2H), 3.55-3.20 (m,10H), 2.40-1.80 (m, 5H) Step 2 (I3). To a solution of 12 (9.9 g, 29.4mmol) in acetone (200 mL, 29.4 mmol) was added HCl (176 mL, 1 M) at 25°C. The mixture was stirred at 25° C. for 18 hours. The reaction mixturewas combined with another batch prepared from 100 mg of 12. Thereaction-mixture was extracted with ethyl acetate (3×150 mL). Thecombined organic phase was washed with water (3×300 mL) and brine (2×200mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give 13(2.4 g, crude) as an oil.

Step 3 (I4). To a stirred solution of 13 (2.4 g, 8.26 mmol) andperchloroethane (3.9 g, 16.5 mmol) in dichloromethane (100 mL) was addedPPh₃ (4.32 g, 16.5 mmol). The mixture was stirred at 0° C. for 15 min.TEA (1.66 g, 16.5 mmol) was then added and the mixture was stirred at25° C. for 18 hours. The mixture was washed with water (2×80 mL), brine(2×80 mL), dried over Na₂SO₄, filtered, concentrated in vacuo to give acrude product, which was purified by flash silica gel chromatography(0-65% EtOAc in PE) to give 14 (630 mg, 32%) as an oil, which was useddirectly for the next step.

Step 4 (I5). To a solution of 14 (530 mg, 1.94 mmol) in AcOH (3 mL) wasadded HBr (6 mL, 35% in AcOH) at 25° C. The mixture was stirred at 25°C. for 2 hours. MTBE (15 mL) was added and a solid was produced. Themixture was filtered. The filter cake was washed with MTBE (15 mL) anddried in vacuo at 50° C. to give 15 (430 mg, crude) as a solid.

¹H NMR (400 MHz, methanol-d₄) δ 8.05 (s, 1H), 7.28 (s, 1H), 5.05-4.85(m, 2H), 3.60-3.45 (m, 2H), 2.60-2.50 (m, 1H), 2.45-2.35 (m, 1H),2.30-2.21 (m, 2H)

Step 5 (Compound 60) To a solution of 2 (200 mg, 0.548 mmol) in DCM (5mL) was added HATU (313 mg, 1.30 mmol) and Et₃N (276 mg, 2.73 mmol) at25° C. The reaction mixture was stirred at 25° C. for 0.5 hour.(R)-2-(pyrrolidin-2-yl)oxazole hydrobromide I5 (180 mg, 0.822 mmmol) wasadded to the reaction mixture at 25° C. The reaction mixture was stirredat 25° C. for 18 hours. The reaction mixture was diluted with EtOAc (30mL) and washed with water (50 mL), brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give the crude product, which waspurified by silica gel chromatography with PE:EtOAc=0:1-1:1 to giveCompound 60 (190 mg) as a solid. The product was further purified bypre-HPLC (Conditions:water (0.05% ammonia hydroxide v/v)-ACN, Column:Phenomenex Gemini C18 250*50 mm*10 um, Gradient Time: 8 min) to giveCompound 60 (98 mg) as a solid. The solid was re-purified by SFC(Column: AD (250 mm*30 mm, 10 um), Conditions: 0.1% NH₃H₂O IPA,Gradient: from 45%, Flow Rate (ml/min): 80 mL/min, 25° C.) to affordCompound 60 (67 mg, 25% as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.60-7.50 (m, 1H), 7.10-6.98 (m, 1H),5.33-5.23 (m, 1H), 3.86-3.70 (m, 1H), 3.66-3.58 (m, 1H), 3.55-3.50 (m,2H), 3.46-3.38 (m, 2H), 2.74-2.42 (m, 2H), 2.30-2.07 (m, 4H), 2.04-1.94(m, 2H), 1.86-1.66 (m, 6H), 1.51-1.32 (m, 8H), 1.28-1.04 (m, 10H),0.77-0.62 (m, 3H).

LCMS Rt=0.977 min in 2.0 min chromatography, 30-90AB, purity 100%; MSESI calcd. for C₂₉H₄₅N₂O₄ [M+H]⁺ 485, found 485.

SFC Rt=1.961 min in 3 min chromatography, AD-H_3UM_4_5_40_4ML, 100% de.(Column: Chiralpak AD-3 50*4.6 mm I.D., 3 um; Mobile phase: A:CO₂B:iso-propanol (0.05% DEA); Gradient: hold 5% for 0.2 min, then from 5%to 40% of B in 1.4 min and hold 40% for 1.05 min, then 5% of B for 0.35min; Flow rate: 4 mL/min Column temp: 40° C.).

Example 56. Synthesis of Compound 61 and Compound 62

Step 1 (J2). Ti(iPrO)₄ (5.31 g, 18.7 mmol) was added to methanamine inMeOH (14.4 mL, 2M, followed by addition of commercially available J1 (2g, 14.4 mmol). After stirring at 25° C. for 3 hours, NaBH₄ (544 mg, 14.4mmol) was added. The mixture was stirred at 25° C. for 18 hours,quenched with water (15 mL). Solid appeared, which was filtered off. Thefiltrate was extracted with EtOAc (2×20 mL). The combined organic phasewas washed with water (2×40 mL), brine (2×40 mL), dried over Na₂SO₄,filtered and concentrated in vacuo to give J2 (2.9 g, impure) as an oil,which was used directly.

Step 2. (Compound 61 and Compound 62). To a solution of C2 (200 mg,0.548 mmol) in DCM (5 mL) was added HATU (312 mg, 0.822 mmol) and TEA(276 mg, 2.73 mmol) at 25° C. After stirring at 25° C. for 0.5 hours,1-(4-fluorophenyl)-N-methylethanamine J2 (134 mg, 0.876 mmmol) was addedat 25° C. The reaction mixture was stirred at 25° C. for 18 hours,diluted with EtOAc (30 mL), washed with water (50 mL) and brine (50 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give thecrude. The crude was purified by silica gel chromatography withPE/EtOAc=0/1-10/1 to give Compound 61 (50 mg, Rf=0.50 in PE/EtOAc=2/1)and Compound 62 (50 mg, Rf=0.45 in PE/EtOAc=2/1) as a solid.

The Compound 61 was further purified by SFC (Column: AD (250 mm*30 mm, 5um), Conditions: 0.1% NH₃H₂O IPA, Gradient: from 35%, Flow Rate(ml/min): 60 mL/min, 25° C.) to afford Compound 61 (25 mg, 9%) as asolid.

The impure Compound 62 (50 mg, 0.100 mmol) was triturated with hexane (3mL) to give Compound 62 (40 mg, 14%) as a solid.

Compound 61

¹H NMR (400 MHz, CDCl₃) δ 7.26-7.22 (m, 2H), 7.09-6.97 (m, 2H),6.17-6.11 (m, 0.9H), 5.28 (s, 0.1H), 3.56-3.50 (m, 2H), 3.46-3.38 (m,2H), 2.74-2.67 (m, 5H), 2.57 (s, 0.5H), 2.36-2.27 (m, 1H), 1.84-1.70 (m,6H), 1.47-1.42 (m, 6H), 1.40-1.32 (m, 4H), 1.30-1.18 (m, 8H), 1.16-1.09(m, 3H), 0.89 (s, 0.6H), 0.79 (s, 3H).

LCMS Rt=1.173 min in 2.0 min chromatography, 30-90AB, purity 100%; MSESI calcd. for C₃₁H₄₇FNO₃ [M+H]⁺ 500, found 500.

SFC Rt=5.128 min in 10 min chromatography, AD_3_IPA_DEA_5_40_25ML,98.36% de. (Column: Chiralpak AD-3 150×4.6 mm I.D., 3 um Mobile phase:A: CO₂ B:iso-propanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 minand hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/minColumn temp.: 35° C.)

Compound 62

¹H NMR (400 MHz, CDCl₃) δ 7.26-7.22 (m, 1.6H), 7.17-7.11 (m, 0.4H),7.06-6.98 (m, 2H), 6.15-6.09 (m, 0.7H), 5.36-5.28 (m, 0.2H), 3.56-3.50(m, 2H), 3.47-3.37 (m, 2H), 2.82-2.65 (m, 5H), 2.40-2.24 (m, 1H),1.89-1.68 (m, 5H), 1.67-1.57 (m, 4H), 1.50-1.17 (m, 16H), 1.16-1.04 (m,3H), 0.82 (s, 3H).

LCMS Rt=1.178 min in 2.0 min chromatography, 30-90AB, purity 100%; MSESI calcd. for C₃₁H₄₇FNO₃ [M+H]⁺ 500, found 500.

Example 57. Synthesis of Compound 63

The synthesis of K1 is disclosed in WO2016/123056.

Step 1 (K2). To a solution of K1 (1 g, 3.13 mmol) in MeOH (10 ml) wasadded HBr (125 mg, 0.626 mmol, 40% in water) and Br₂ (500 mg, 3.19 mmol)at 25° C. The mixture was stirred at 25° C. for 16 hrs. The mixture wasquenched with sat. aqueous NaHCO₃ (10 mL), treated with water (20 mL),extracted with EtOAc (2×20 mL). The combined organic phase was washedwith brine (20 mL), dried over anhydrous Na₂SO₄, filtered, concentratedin vacuo to afford K2 (1.2 g) as a solid, which was used directly forthe next step.

Step 2 (Compound 63). To a solution of K2 (100 mg, 0.251 mmol) in DMF (5mL) was added N-methylaniline (32.2 mg, 0.301 mmol) and TEA (76.1 mg,0.753 mmol) at 25° C. The mixture was stirred at 25° C. for 18 h to givea yellow solution. The mixture was purified by prep-HPLC (Column: Gemini150*25 5 u; Conditions: water (0.05% HCl)-ACN; Gradient 27%-52% B;FlowRate (ml/min): 30) to afford Compound 63 (4 mg, 4%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.36-7.29 (m, 2H), 7.17-7.08 (m, 2H),7.04-6.98 (m, 1H), 4.21-4.11 (m, 2H), 3.18 (s, 3H), 2.56-2.48 (m, 1H),2.19-2.09 (m, 1H), 1.90-1.74 (m, 3H), 1.69-1.63 (m, 2H), 1.52-1.24 (m,10H), 1.20 (s, 3H), 1.13-0.92 (m, 6H), 0.73-0.61 (m, 2H), 0.55 (s, 3H)

LCMS Rt=2.147 in in 3.0 min chromatography, 10-80AB, purity 100%, MS ESIcalcd. for C₂₈H₄₂NO₂ [M+H]⁺ 424, found 424.

Example 58. Synthesis of Compound 64

Step 1 (Compound 64). To a solution of K2 (60 mg, 0.151 mmol) in DMF (2mL) was added DIPEA (25.3 mg, 0.196 mmol). The mixture was stirred for10 min at 20° C. To the mixture was added aniline (18.2 mg, 0.196 mmol).The mixture was stirred another 16 hours at 20° C. The mixture waspoured into water (10 mL) and extracted with EtOAc (2×10 mL). Thecombined organic layers were washed with brine (2×10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by prep-HPLC (column: Phenomenex Gemini C18 250*50 mm*10 um,gradient: 70-100% B, Conditions: water (0.05% ammonia hydroxidev/v)-ACN, flow rate: 30 mL/min) to give Compound 64 (10 mg, 16.1%) as asolid.

¹H NMR (400 MHz, CDCl₃) δ 7.21 (t, J=8 Hz, 2H), 7.76-7.69 (m, 1H),6.62-6.58 (m, 2H), 4.70 (brs, 1H), 4.41-3.86 (m, 2H), 2.62-2.55 (m, 1H),2.29-2.19 (m, 1H), 2.01-1.92 (m, 1H), 1.88-1.64 (m, 7H), 1.47-1.16 (m,10H), 1.13-0.96 (m, 6H), 0.79-0.64 (m, 5H).

LCMS Rt=1.173 min in 2 min chromatography, 30-90AB, purity 95%, MS ESIcalcd. for C₂₇H₄₀NO₂ [M+H]⁺ 410, found 410.

Example 59. Synthesis of Compound 65

The synthesis of L1 is disclosed in WO2015/27227.

Step 1 (L2). To a solution of L1 (1.2 g, 2.77 mmol) in MeOH (10 ml) wasadded HBr (110 mg, 0.554 mmol, 40% in water) and Br₂ (442 mg, 2.82 mmol)at 25° C. After stirring at 25° C. for 16 hrs, the mixture was quenchedwith sat.aq NaHCO₃ (10 mL), treated with water (20 mL), extracted withEtOAc (2×20 mL). The combined organic phase was washed with brine (20mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo toafford L2 (1.4 g) as a solid which was used directly for the next step.

Step 2 (Compound 65) To a solution of L2 (100 mg, 0.219 mmol) in DMF (5mL) was added N-methylaniline (28 mg, 0.262 mmol) and TEA (66.4 mg, 657mmol) at 25° C. The mixture was stirred at 25° C. for 18 h to give ayellow solution. The mixture was purified by prep-HPLC (Column: Gemini150*25 5 u; Conditions: water (0.05% HCl)-ACN; Gradient 62%-87% B;FlowRate(ml/min): 30) to afford (Compound 65) (3 mg, 3%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.21-7.17 (m, 2H), 6.76-6.70 (m, 1H),6.66-6.60 (m, 2H), 4.13-3.95 (m, 2H), 3.53-3.50 (s, 1H), 3.43-3.35 (m,3H), 3.01 (s, 3H), 2.65-2.52 (m, 1H), 2.22-2.13 (m, 1H), 2.05-1.95 (m,2H), 1.75-1.63 (m, 3H), 1.52-1.45 (m, 5H), 1.26-1.14 (m, 15H), 1.00-0.93(m, 1H), 0.88-0.77 (m, 2H), 0.67 (s, 3H).

LCMS Rt=1.254 in in 2.0 min chromatography, 30-90AB, purity 95%, MS ESIcalcd. for C₃₁H₄₈NO₃ [M+H]⁺ 482, found 482.

Example 60. Synthesis of Compound 66

Step 1 (Compound 66). To a solution of DIPEA (18.2 mg, 0.141 mmol) inDMF (1.5 mL) was added aniline (20.3 mg, 0.218 mmol) at 10° C. under N₂.After stirring at 10° C. for 30 min, L2 (50 mg, 0.109 mmol) in DMF (1.5mL) was added. The reaction mixture was stirred at 40° C. for 16 hours.Another batch of DIPEA (36.5 mg, 0.283 mmol) and aniline (40.6 mg, 0.436mmol) were added to the reaction mixture. The reaction mixture washeated to 50° C. and stirred at this temperature for another 16 hours.The reaction mixture was treated with water (5 mL) and extracted withEtOAc (2×10 mL). The combined organic layers were washed with brine (10mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give thecrude. The crude was purified by prep-HPLC (Conditions: Water (0.05%ammonia hydroxide v/v-ACN), Column: Phenomenex Gemini C18 250*50 mm*10μm, Gradient Time: 8 min). The solvent was removed to give Compound 66(19 mg, 37%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.19 (t, 2H), 6.72 (t, 1H), 6.60 (d, 2H),4.00-3.86 (m, 2H), 3.52-3.49 (m, 1H), 3.41-3.35 (m, 3H), 2.57 (br t,1H), 2.29-2.19 (m, 1H), 2.07-1.92 (m, 2H), 1.71 (br d, 4H), 1.65-1.59(m, 3H), 1.51-1.46 (m, 4H), 1.39-1.24 (m, 5H), 1.23-1.19 (m, 5H), 1.15(t, 4H), 1.12-1.06 (m, 1H), 1.03-0.94 (m, 1H), 0.65 (s, 3H).

LCMS Rt=2.391 min in 3 min chromatography, 30-90CD, purity 97.8%, MS ESIcalcd. for C₃₀H₄₆NO₃ [M+H]⁺ 468, found 468.

Example 61. Synthesis of Compound 67 and Compound 68

Step 1 (M2). To a mixture of M2 (5 g, 17.4 mmol) and CsF (1.32 g, 8.70mmol) in THF (50 mL) was added drop-wise TMSCF₃ (6.17 g, 43.4 mmol) at0° C. The mixture was stirred at 25° C. for 1 h. To the mixture wasadded TBAF (52 mL, 1 M in THF, 52 mmol). The mixture was stirred at 25°C. for another 2 hrs. The mixture was poured into water (100 mL) andextracted with EtOAc (2×50 mL). The combined organic phase was washedwith brine (2×50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel chromatography(PE/EtOAc=5/1-3/1) to give impure M2 (4.6 g) as a solid. The crudeproduct was re-crystallized from MeCN (3 mL) at 25˜50° C. to give M2(2.64 g, 40%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.16-5.08 (m, 1H), 2.40-2.13 (m, 3H),2.05-1.74 (m, 6H), 1.73-1.42 (m, 12H), 1.30-1.04 (m, 6H), 0.88 (s, 3H).

Step 2 (M3). To a solution of M2 (1 g, 2.80 mmol) in THF (30 mL) wasadded 9-BBN dimer (2 g, 8.19 mmol) at 0° C. under N₂. The solution wasstirred at 65° C. for 1 h. After cooling the mixture to 0° C., asolution of NaOH (6 mL, 5 M, 30 mmol) was added very slowly. H₂O₂ (4 g,35.2 mmol, 30% in water) was added slowly and the inner temperature wasmaintained below 10° C. The mixture was stirred at 60° C. under N₂ for 1hour. The mixture was cooled to 30° C. and water (30 mL) was added. Thereaction mixture was extracted with EtOAc (30 mL). The organic layer waswashed with brine (2×20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuum to afford M3 (1.43 g, crude) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 3.88-3.65 (m, 3H), 1.96-1.76 (m, 6H),1.73-1.38 (m, 10H), 1.27-1.02 (m, 11H), 0.67 (S, 3H).

Step 3 (M4). To a solution of M3 (1.43 g, 3.81 mmol) in DCM (15 mL) wasadded DMP (3.23 g, 7.62 mmol) slowly at 25° C. The mixture was stirredat 25° C. for 1 hour. The mixture was poured into saturated Na₂S₂O₃ (30mL) and extracted with DCM (2×30 mL). The combined organic layer waswashed with brine (2×30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by column(PE/EtOAc=5/1˜3/1) to give M4 (570 mg, 40%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 2.57-2.51 (m, 1H), 2.20-1.93 (m, 8H),1.86-1.44 (m, 13H), 1.81-1.06 (m, 6H), 0.62 (s, 3H).

Step 4 (M5). Liquid bromine (1.91 g, 12.0 mmol) was added slowly to avigorously stirred aqueous sodium hydroxides solution (16.0 mL, 3 M,48.2 mmol) at 0° C. When all the bromine dissolved, the mixture wasdiluted with cold dioxane (4.5 mL) and added slowly to a stirredsolution of M4 (1.5 g, 4.02 mmol) in dioxane (6 mL) and water (4.5 mL).The homogeneous yellow solution became colorless slowly and a whiteprecipitate formed. The reaction mixture was stirred at 25° C. for 5hrs. The remaining oxidizing reagent was quenched with aqueous Na₂S₂O₃(30 mL) and the mixture was then heated to 80° C. until the solidmaterial dissolved. The solution was acidified with aqueous HCl (3 M, 30mL), and a solid was precipitated. The solid was filtered and washedwith water (3×50 mL) to give a solid which was dried with toluene (2×40mL) in vacuo to afford M5 (1.1 g, 73%) as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ 11.89 (br s, 1H), 5.73 (s, 1H), 2.29 (t,J=9.4 Hz, 1H), 1.99-1.87 (m, 4H), 1.85-1.51 (m, 7H), 1.49-1.32 (m, 5H),1.30-1.15 (m, 4H), 1.12-0.96 (m, 3H), 0.64 (s, 3H).

Step 5 (Compound 67). To a solution of M5 (200 mg, 0.534 mmol) in DCM (3mL) was added commercially available (S)-4-(1-aminoethyl)benzonitrilehydrochloride (146 mg, 0.801 mmol), TEA (269 mg, 2.66 mmol) and HATU(304 mg, 0.801 mmol). The mixture was stirred at 25° C. for 1 h. Themixture was washed with water (1 mL) and concentrated in vacuo. Theresidue was purified by prep-HPLC (Instrument: FB; Column: PhenomenexGemini C18 250*50 mm*10 um; Conditions: water (0.05% ammonia hydroxidev/v)-ACN; Begin B: 58; End B: 88; Gradient Time (min): 8; 100% B HoldTime (min): 2; FlowRate(ml/min): 30; Injections: 7) to give Compound 67(170 mg, 63%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.4 Hz,2H), 5.53 (d, J=7.2 Hz, 1H), 5.20-5.08 (m, 1H), 2.21-1.89 (m, 5H),1.86-1.61 (m, 8H), 1.55-1.39 (m, 8H), 1.30-1.04 (m, 7H), 0.55 (s, 3H).

LCMS Rt=1.257 min in 2 min chromatography, 10-80AB, purity 100%, MS ESIcalcd. for C₂₉H₃₈F3N₂O₂[M+H]⁺ 503, found 503.

HPLC Rt=6.04 min in 10 min chromatography, 10-80, 100% d.e.

Step 6 (Compound 68). To a solution of Compound 67 (120 mg, 0.238 mmol)in DMF (1 mL) was added NaH (9.51 mg, 60%, 0.238 mmol). The mixture wasstirred at 20° C. for 15 min. MeI (33.7 mg, 0.238 mmol) was then addedand the reaction was stirred at 20° C. for 15 min. The mixture wasquenched with water (5 mL) and extracted with EtOAc (2 mL). The organiclayer was separated, concentrated in vacuo and purified by flash silicagel chromatography (0˜30% EtOAc in PE) to give Compound 68 (10 mg, 8%)as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.0 Hz,2H), 6.16 (d, J=7.6 Hz, 1H), 3.36 (s, 3H), 2.80-2.67 (m, 4H), 2.39-2.24(m, 1H), 2.10-1.98 (m, 1H), 1.98-1.88 (m, 1H), 1.81-1.62 (m, 8H),1.52-1.02 (m, 15H), 0.82 (s, 3H).

LCMS Rt=1.254 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₃₁H₄₂F3N₂O₂[M+H]⁺ 531, found 531.

Example 62. Synthesis of Compound 69 and Compound 70

Step 1 (N2). A solution of commercially available 4-acetylbenzonitrileN1 (1 g, 6.88 mmol) in MeNH₂ (20.6 mL, 41.2 mmol, 2M in EtOH) wasstirred at 20° C. for 16 hrs. NaBH₄ (1.30 g, 34.4 mmol) was added andthe mixture was stirred at 20° C. for 2 h, quenched with 50% NH₄Cl (50mL) and extracted with EtOAc (2×20 mL). The combined organic phase waswashed with brine (50 mL), dried over Na₂SO₄, filtered, concentrated andpurified by silica gel chromatography (0-20% of EtOAc in PE) to giveimpure compound (900 mg, 82%) as an oil, which was used directly fornext step.

¹H NMR (400 MHz, CDCl₃) δ 7.66-7.58 (m, 2H), 7.46-7.40 (m, 2H),3.75-3.67 (m, 1H), 2.42-2.36 (m, 1H), 2.29 (s, 3H), 1.37-1.31 (m, 3H).

Step 2. (Compound 69 and Compound 70). To a solution of M2 (160 mg,0.427 mmol) in DCM (5 mL) was added HATU (249 mg, 0.640 mmol), TEA (215mg, 2.13 mmol and 4-(1-(methylamino)ethyl)benzonitrile N2 (136 mg, 0.854mmol). After stirring at 25° C. for 1 h, the reaction mixture wasquenched with water (20 mL) and extracted with DCM (3×5 mL). Thecombined organic phase was washed with HCl (2×20 mL, 2 M), dried overNa₂SO₄, filtered, concentrated and purified by preparative TLC(PE/EtOAc=2/1) to give Compound 69 (60 mg) and Compound 70 (35 mg, 16%)as an oil. 60 mg Compound 69 was separated by SFC (column: AD (250 mm*30mm, 5 um), gradient: 50-50% B (A=0.05% NH₃/H₂O, B=MeOH), flow rate: 60mL/min) to give impure Compound 69 (35 mg), which was further separatedby SFC (column: AD (250 mm*30 mm, 5 um), gradient: 50-50% B (A=0.05%NH₃/H₂O, B=MeOH), flow rate: 60 mL/min) to give pure Compound 69 (16 mg,7%) as a solid.

Compound 69

¹H NMR (400 MHz, CDCl₃) δ 7.72-7.57 (m, 2H), 7.42-7.33 (m, 2H),6.22-6.12 (m, 0.9H), 5.37-5.28 (m, 0.1H), 2.78-2.57 (m, 4H), 2.37-2.24(m, 1H), 2.13-1.99 (m, 2H), 1.97-1.88 (m, 1H), 1.87-1.64 (m, 8H),1.56-1.41 (m, 8H), 1.37-1.06 (m, 7H), 0.92-0.75 (m, 3H).

LCMS Rt=3.583 min in 7.0 min chromatography, 30-90AB, purity 100%, MSESI calcd. for C₃₀H₄₀F3N₂O₂[M+H]⁺ 517, found 517.

Compound 70

¹H NMR (400 MHz, CDCl₃) δ 7.68-7.60 (m, 2H), 7.41-7.36 (m, 1.5H),7.31-7.27 (m, 0.5H), 6.20-6.11 (m, 0.8H), 5.41-5.32 (m, 0.2H), 2.77-2.68(m, 4H), 2.43-2.44 (m, 1H), 2.08-1.89 (m, 3H), 1.85-1.61 (m, 9H),1.53-1.44 (m, 6H), 1.41-1.24 (m, 4H), 1.24-1.02 (m, 4H), 0.81 (s, 3H).

LCMS Rt=3.489 min in 7.0 min chromatography, 30-90AB, purity 100%, MSESI calcd. for C₃₀H₄₀F3N₂O₂[M+H]⁺ 517, found 517.

Example 63. Synthesis of Compound 71 and 72

Step 1 (Compound 71). To a solution of M2 (200 mg, 0.534 mmol) in DCM (5mL) was added HATU (312 mg, 0.801 mmol), Et₃N (268 mg, 2.66 mmol and(R)-4-(1-aminoethyl)benzonitrile (117 mg, 0.801 mmol). After stirring at25° C. for 1 h, the reaction mixture was quenched with water (20 mL) andextracted with DCM (3×5 mL). The combined organic phase was dried overNa₂SO₄, filtered, concentrated and purified prep-HPLC (column: YMC-ActusTriart C18 100*30 mm*5 um), gradient: 75-100% B (A=water (0.05% HCl),B=MeCN), flow rate: 25 mL/min) to give Compound 71 (200 mg, 75%) as asolid.

¹H NMR (400 MHz, CDCl₃) δ 7.65-7.59 (m, 2H), 7.44-7.39 (m, 2H),5.52-5.45 (m, 1H), 5.21-5.12 (m, 1H), 2.20-2.10 (m, 2H), 2.08-1.99 (m,2H), 1.97-1.89 (m, 2H), 1.87-1.78 (m, 3H), 1.77-1.58 (m, 5H), 1.54-1.45(m, 6H), 1.35-1.05 (m, 8H), 0.69 (s, 3H).

LCMS Rt=1.287 min in 2.0 min chromatography, 10-80AB, purity 99%, MS ESIcalcd. for C₂₉H₃₈F₃N₂O₂[M+H]⁺ 503, found 503.

Example 64. Synthesis of Compound 73

Step 1 (02): To a solution of 01 (50 g, 157 mmol) in MeOH (500 mL) wasadded 4-methylbenzenesulfonic acid (2.70 g, 15.7 mmol) at 25° C. Themixture was stirred at 65° C. for 1 h. The reaction mixture was cooledto 25° C. and TEA (2.16 mL, 15.7 mmol) was added. The mixture wasstirred for 0.5 h. The precipitate was collected by filtration andwashed with methanol (2×100 mL) to give 02 (50 g, crude) as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ 3.25-3.05 (m, 6H), 2.60-2.40 (m, 1H),2.20-2.05 (m, 4H), 2.00-1.95 (m, 1H), 1.90-1.80 (m, 1H), 1.75-1.50 (m,6H), 1.49-1.05 (m, 12H), 1.04-0.95 (m, 1H), 0.78 (s, 3H), 0.59 (s, 3H).

Step 2 (03): To a solution of bromo(methyl)triphenylphosphorane (73.2 g,205 mmol) in THF (500 mL) was added t-BuOK (23.0 g, 205 mmol) at 25° C.The mixture was heated to 45° C. and stirred for 1 h. 02 (50 g, 137mmol) was added. The mixture was stirred at 45° C. for 2 hrs. Themixture was quenched with NH₄Cl (200 mL) and extracted with THF (3×100mL). The organic layer was washed brine (200 mL), dried over Na₂SO₄ andfiltered to give a mixture of products including 03 (50 g, 500 mL),which was used in next step without further purification.

Step 3 (O4): To a solution of the mixture containing O3 (50 g, 138 mmol)in THF (500 mL) was added aq. HCl (207 mL, 1 M in water). The mixturewas stirred at 25° C. for 0.5 h. The mixture was filtered and the filtercake was dissolved in DCM (200 mL) and washed with brine (100 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuum to afford O4(39 g, 90%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 4.84 (s, 1H), 4.70 (s, 1H), 2.45-2.20 (m, 3H),2.15-2.00 (m, 3H), 1.90-1.65 (m, 8H), 1.60-1.50 (m, 2H), 1.45-1.05 (m,8H), 1.00 (s, 3H) 0.90-0.85 (m, 1H), 0.80-0.75 (m, 1H), 0.58 (s, 3H).

Step 4 (05): To a solution of 04 (27 g, 85.8 mmol) in THF (200 mL) wasadded CsF (25.9 g, 171 mmol) and TMSCF₃ (24.3 g, 171 mmol). The mixturewas stirred at 10° C. for 1 h. To the mixture was added water (10 mL)and TBAF.3H₂O (30 g). The mixture was stirred at 30° C. for another 2hrs. The mixture was concentrated in vacuum. The residue was dissolvedin EtOAc (500 mL), washed with water (2×500 mL), dried over Na₂SO₄,filtered, concentrated in vacuum and purified by flash column (DCM/EtOAc(1:1) in PE, 0˜10%) to give 05 (27 g, 82%) and by-product O5A (3.5 g,11%) as solids.

O5:

¹H NMR (400 MHz, CDCl₃) δ 4.84 (s, 1H), 4.70 (s, 1H), 2.12-1.94 (m, 3H),1.89-1.78 (m, 2H), 1.75 (s, 3H), 1.72-1.60 (m, 5H), 1.58-1.48 (m, 2H),1.45-1.09 (m, 10H), 1.01-0.89 (m, 1H), 0.85 (s, 3H), 0.78-0.68 (m, 1H),0.56 (s, 3H).

Step 5 (06). To a solution of 05 (1 g, 2.6 mmol) in DCM (30 mL) and MeOH(30 mL) was added NaHCO₃ (1 g, 11.9 mmol). To the mixture was bubbledozone (1 atm) at −78° C. until the mixture turned blue (ca. 2 min). N₂was bubbled for an additional 5 min until the mixture turned colorless.To the mixture was added Me₂S (1.3 g, 20.9 mmol), and the mixture wasstirred at 15° C. for 16 h. The mixture was filtered and concentrated invacuo, triturated with MeCN (10 mL) to give 06 (0.8 g, 80%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 2.52 (t, J=8.8 Hz, 1H), 2.21-2.13 (m, 1H),2.11 (s, 3H), 2.07-1.97 (m, 1H), 1.85-1.52 (m, 10H), 1.47-1.11 (m, 9H),1.03-0.89 (m, 1H), 0.86-0.76 (m, 4H), 0.61 (s, 3H).

Step 6 (07). To a solution of 06 (0.8 g, 2.06 mmol) in MeOH (10 ml) wasadded HBr (82.2 mg, 0.412 mmol, 40% in water) and Br₂ (329 mg, 2.10mmol) at 25° C. The mixture was stirred at 25° C. for 16 hrs. Themixture was quenched with sat. aqueous NaHCO₃ (10 mL), treated withwater (20 mL), extracted with EtOAc (2×20 mL). The combined organicphase was washed with brine (20 mL), dried over anhydrous Na₂SO₄,filtered, concentrated in vacuo to afford 07 (0.9 g, 94%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 3.95-3.90 (m, 2H), 2.90-2.75 (m, 1H),2.25-2.10 (m, 1H), 1.95-1.85 (m, 1H), 1.80-1.50 (m, 10H), 1.45-1.15 (m,9H), 1.00-0.75 (m, 5H), 0.65 (s, 3H).

Step 7 (Compound 73). To a solution of DIPEA (21.4 mg, 0.166 mmol) inDMF (3 mL) was added PhNH₂ (23.8 mg, 0.256 mmol) at 25° C. The reactionmixture was stirred at 25° C. for 30 mins. 07 (60 mg, 0.128 mmol) wasadded. The reaction mixture was stirred at 40° C. for 10 hrs. Thereaction mixture was quenched with water (5 mL). The aqueous phase wasextracted with EtOAc (3×10 mL). The combined organic phase was washedwith brine (2×10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was triturated with H₂O (10 mL) at 25° C. togive Compound 73 (20 mg, crude) as a solid, which was purified by HPLC(Instrument: BQ; Method: Column YMC-Actus Triart C18 100*30 mm*5 um;Conditions: water (0.05% HCl)-ACN; Gradient 80%-100% B; Gradient Time(min): 9.5) to obtain Compound 73 (9 mg, 15%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.19 (t, J=8.0 Hz, 2H), 6.72 (t, J=8.0 Hz,1H), 6.60 (d, J=8.0 Hz, 2H), 4.69 (s, 1H), 4.02-3.85 (m, 2H), 2.61-2.53(m, 1H), 2.30-2.18 (m, 1H), 2.03-1.92 (m, 1H), 1.83-1.60 (m, 9H),1.46-1.16 (m, 10H), 1.04-0.92 (m, 1H), 0.84-0.77 (m, 4H), 0.64 (s, 3H).

LCMS Rt=1.228 min in 2.0 min chromatography, 30-90AB, purity 100%, MSESI calcd. For C₂₈H₃₉F₃NO₂ [M+H]⁺ 478, found 478.

Example 65. Synthesis of Compound 74

Step 1 (Compound 74). To a solution of DIPEA (21.4 mg, 0.166 mmol) inDMF (3 mL) was added PhNHMe (27.3 mg, 0.256 mmol) at 25° C. The reactionmixture was stirred at 25° C. for 0.5 hour. 03 (60 mg, 0.128 mmol) wasadded. The reaction mixture was stirred at 40° C. for 20 h and quenchedwith water (5 mL). The aqueous phase was extracted with EtOAc (3×10 mL).The combined organic phase was washed with brine (2×10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was trituratedwith H₂O (10 mL) at 25° C. to give Compound 74 (21 mg, crude) as asolid. The crude product was purified by HPLC (Instrument: BQ; Method:Column YMC-Actus Triart C18 100*30 mm*5 um; Condition: water(0.05%HCl)-ACN; Gradient 80%-100% B; Gradient Time (min): 9.5) to obtainCompound 74 (8 mg, 38%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.23-7.17 (m, 2H), 6.71 (t, J=8.0 Hz, 1H),6.60 (d, J=8.0 Hz, 2H), 4.11-3.96 (m, 2H), 2.99 (s, 3H), 2.64-2.57 (m,1H), 2.22-2.08 (m, 1H), 1.99-1.94 (m, 1H), 1.86-1.57 (m, 9H), 1.46-1.19(m, 9H), 1.18-0.89 (m, 2H), 0.85-0.76 (m, 4H), 0.67 (s, 3H) LCMSRt=1.227 min in 2.0 min chromatography, 30-90AB, purity 100% ESI calcd.For C₂₉H₄₁F₃NO₂ [M+H]⁺ 492 found 492.

Example 66. Synthesis of Compound 75

The synthesis of P1 is disclosed in WO2016/123056.

To a solution of DIPEA (18.8 mg, 146 μmol) in DMF (3 mL) was addedN-methylaniline (24.2 mg, 226 μmol) at 10° C. under N₂ at 10° C. Themixture was stirred at this temperature for 30 mins. Then P1 (50 mg,0.113 mmol) was added. The mixture was heated at 60° C. for 16 hrs. Themixture was concentrated to give light yellow oil, which was purified byHPLC (Column: Xtimate C18 150*25 mm*5 um; Conditions: water (0.05%HCl)-ACN; Gradient 63%-88% B; Gradient Time (min): 9.5) to affordCompound 75 (7.00 mg, 13%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.35-7.20 (m, 2H), 7.05-6.86 (m, 3H),4.08-4.03 (m, 2H), 3.58-3.47 (m, 1H), 3.32 (s, 3H), 3.20-3.12 (m, 1H),3.11 (s, 3H), 2.54 (brs, 1H), 2.20-2.03 (m, 1H), 1.90 (s, 3H), 1.82-1.33(m, 12H), 1.33-1.06 (m, 10H), 0.58 (s, 3H).

LCMS Rt=0.943 min in 1.5 min chromatography, 5-95 AB, purity 100%, MSESI calcd. for C₃₀H₄₆NO₃ [M+H]⁺ 468, found 468.

Example 67. Synthesis of Compound 76

Step 1 (Compound 76) To a solution of P1 (100 mg, 0.226 mmol) in DMF (5mL) was added aniline (25.2 mg, 0.271 mmol) and TEA (68.6 mg, 0.678mmol) at 25° C. under N₂. The mixture was stirred at 25° C. for 18 h togive a yellow solution. The mixture was purified by prep-HPLC(Column:Gemini 150*25 5 u; Conditions: water(0.05% HCl)-ACN; Gradient66%-91% B; Gradient Time (min): 30) to afford Compound 76 (15 mg, 15%)as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.40-7.33 (m, 4H), 7.24-7.18 (m, 1H),4.24-4.18 (m, 2H), 3.53-3.48 (m, 1H), 3.31 (s, 3H), 3.18-3.13 (m, 1H),2.55-2.45 (m, 1H), 2.22-2.12 (m, 1H), 1.92-1.84 (m, 3H), 1.80-1.71 (m,3H), 1.63-1.40 (m, 10H), 1.28-1.15 (m, 10H), 0.58 (s, 3H).

LCMS Rt=2.014 in in 3.0 min chromatography, 10-80AB, purity 100%, MS ESIcalcd. for C₂₉H₄₄NO₃ [M+H]⁺ 454, found 454.

Example 68. Synthesis of Compound 77

The synthesis of Q1 is disclosed in WO2015/27227 A1.

To a solution of Q1 (80 mg, 0.1614 mmol) in DMF (1 mL) was added DIPEA(52.1 mg, 0.4035 mmol). The mixture was stirred at 20° C. for 10 min.Aniline (37.5 mg, 0.4035 mmol) was added to the reaction mixture. Afterstirring at 20° C. another 12 hours, the mixture was poured into water(20 mL) and extracted with EtOAc (2×20 mL). The combined organic layerswere washed with brine (2×20 mL), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by HPLC (column:Phenomenex Gemini C18 250*50 mm*10 um, gradient: 78-88% B, Conditions:water (0.05% ammonia hydroxide v/v)-ACN, flow rate: 30 mL/min) to giveCompound 77 (35 mg, 43%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.22-7.17 (m, 2H), 6.76-6.70 (m, 1H),6.62-6.59 (m, 2H), 3.28-3.23 (m, 1H), 4.68 (brs, 1H), 4.0-3.87 (m, 2H),3.50-3.48 (m, 1H), 3.31 (s, 3H), 2.61-2.54 (m, 1H), 2.29-1.68 (m, 11H),1.65-1.21 (m, 12H), 0.65 (s, 3H).

LCMS Rt=2.273 min in 3 min chromatography, 30-90CD, purity 100%, MS ESIcalcd. for C₂₉H₄₁F₃NO₃ [M+H]⁺ 508, found 508.

Example 69. Synthesis of Compound 78

The synthesis of R1 is disclosed in WO2015/27227 A1.

Step 1 (R2). Liquid bromine (1.9 g, 0.61 mL, 11.9 mmol) was added slowlyto a vigorously stirred aqueous solution of sodium hydroxide (9 mL, 4 M,36 mmol) at 0° C. When all the bromine dissolved, the mixture wasdiluted with cold dioxane (0.75 mL) and added slowly to a stirredsolution of R1 (500 mg, 1.2 mmol) in dioxane (1 mL) and water (0.75 mL).The homogeneous yellow solution became colorless slowly and a whiteprecipitate formed. The reaction mixture was stirred at 25° C. for 16hours. The remaining oxidizing reagent was quenched with aqueous Na₂S₂O₃(1.5 mL) and the mixture was then heated at 80° C. until the solidmaterial dissolved. Acidification of the solution with hydrochloric acid(3 N) furnished a white precipitate. The solid was filtered and washedwith water (3×20 mL) to give a solid, which was dried in vacuo to giveR² (600 mg, crude) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.70 (s, 1H), 3.59-3.44 (m, 1H), 3.26-3.15 (m,4H), 2.34-2.23 (m, 1H), 2.07-1.32 (m, 17H), 1.27-0.98 (m, 6H), 0.68-0.56(m, 3H).

LCMS Rt=0.948 min in 2 min chromatography, 30-90AB, purity 97%, MS ESIcalcd. for C₂₂H₃₂F₃O₄ [M−H]⁻ 417, found 417.

Step 2 (Compound 78). To R² (60 mg, 0.14 mmol) in DCM (3 mL) was addedHATU (81.3 mg, 0.21 mmol) and Et₃N (72.3 mg, 0.71 mmol) at 25° C. Afterstirring at 25° C. for 0.5 hour, aniline (21.2 mg, 0.228 mmol) was addedat 25° C. The reaction mixture was stirred at 40° C. for 10 hours andtreated with water (10 mL). The mixture was extracted with EtOAc (2×10mL). The combined organic phase was washed with water (2×10 mL) andsaturated brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by HPLC (column: Xtimate C18150*25 mm*5 um), Conditions: water(0.225% FA)-ACN, gradient: 75-95% B,Gradient Time: 13 mins, 100% B Hold Time: 2.5 min, flow rate: 25 mL/min)to give Compound 78 (21 mg, 29%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.54-7.46 (m, 2H), 7.36-7.29 (m, 2H),7.13-7.06 (m, 1H), 6.93 (s, 1H), 3.54-3.48 (m, 1H), 3.30 (s, 3H),3.29-3.25 (m, 1H), 2.34-2.23 (m, 2H), 2.17-2.08 (m, 1H), 2.07-1.96 (m,4H), 1.89-1.61 (m, 7H), 1.51-1.42 (m, 3H), 1.41-1.04 (m, 7H), 0.75 (s,3H).

LCMS Rt=1.101 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₈H₃₉F₃NO₃ [M+H]⁺ 494, found 494.

Example 70. Synthesis of Compound 79

Step 1 (Compound 79). To R² (100 mg, 0.23 mmol) in DCM (3 mL) was addedHATU (135 mg, 0.35 mmol) and Et₃N (120 mg, 1.19 mmol) at 25° C. Afterstirring at 25° C. for 0.5 hour, N-methyl-1-phenylmethanamine (46 mg,0.38 mmol) was added at 25° C. The reaction mixture was stirred at 40°C. for 10 hours and treated with water (10 mL). The mixture wasextracted with EtOAc (2×10 mL). The combined organic phase was washedwith water (2×10 mL) and saturated brine (10 mL), dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by HPLC(column: Xtimate C18 150*25 mm*5 um), Conditions: water(0.225% FA)-ACN,gradient: 70-100% B, Gradient Time: 13 mins, 100% B Hold Time: 2.5 min,flow rate: 25 mL/min) to give Compound 79 (46 mg, 37%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.39-7.28 (m, 2H), 7.25-7.17 (m, 2H),7.16-7.08 (m, 1H), 5.08-4.89 (m, 1H), 4.37-4.21 (m, 1H), 3.56-3.48 (m,1H), 3.31 (s, 3H), 3.29-3.23 (m, 1H), 3.01-2.91 (m, 3H), 2.83-2.67 (m,1H), 2.41-2.27 (m, 1H), 2.15-1.86 (m, 4H), 1.84-1.59 (m, 7H), 1.54-1.18(m, 10H), 1.16-0.98 (m, 1H), 0.80 (s, 3H).

LCMS Rt=1.110 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₃₀H₄₃F₃NO₃ [M+H]⁺ 522, found 522.

Example 71. Synthesis of Compound 80

Step 1 (Compound 80). To R2 (100 mg, 0.23 mmol) in DCM (3 mL) was addedHATU (135 mg, 0.35 mmol) and Et₃N (120 mg, 1.19 mmol) at 25° C. Afterstirring at 25° C. for 0.5 hour, cyclohexanamine (37.6 mg, 0.38 mmol)was added at 25° C. The reaction mixture was stirred at 25° C. for 10hours and treated with water (10 mL). The mixture was extracted withEtOAc (2×10 mL). The combined organic phase was washed with water (2×10mL) and saturated brine (10 mL), dried over anhydrous Na₂SO₄, filteredand concentrated. The residue was purified by trituration with MeCN (5mL) to give Compound 80 (49 mg, 40%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.16-5.07 (m, 1H), 3.87-3.73 (m, 1H),3.54-3.47 (m, 1H), 3.30 (s, 3H), 3.29-3.24 (m, 1H), 2.23-1.86 (m, 9H),1.79-1.62 (m, 8H), 1.55-1.33 (m, 8H), 1.29-1.02 (m, 9H), 0.66 (s, 3H).

LCMS Rt=1.107 min in 2 min chromatography, 30-90AB, purity 97%, MS ESIcalcd. for C₂₈H₄₅F₃NO₃ [M+H]⁺ 500, found 500.

Example 72. Synthesis of Compound 81 and Compound 82

The synthesis of S1 is disclosed in Russian Chemical Bulletin, 2013,vol. 62, 9 p. 2086-2087.

Step 1 (S2). To a solution of S1 (5.00 g, 13.9 mmol) in THF (100 mL) wasadded Pd/C (wet, 1.5 g). The mixture was stirred under H₂ (15 psi) at25° C. for 16 hours. The mixture was filtered through a pad of celiteand the filtrate was concentrated in vacuo to afford S2 (4.80 g, 96%) asa solid.

¹H NMR (400 MHz, CDCl₃) δ 4.03-3.80 (m, 4H), 3.74 (s, 2H), 2.74-2.66 (m,1H), 2.40-1.98 (m, 5H), 1.98-1.56 (m, 6H), 1.56-1.05 (m, 12H), 1.01 (s,3H), 0.78 (s, 3H).

Step 2 (S3). A solution of trimethylsulfonium iodide (5.42 g, 26.6 mmol)and NaH (1.06 g, 26.6 mmol, 60% purity) in DMSO (50 mL) was stirred at25° C. for 1.0 h under N₂. To the reaction mixture was added a solutionof S2 (4.80 g, 13.3 mmol) in DMSO (20 mL) and the mixture was stirred at60° C. for 4 hrs. The reaction was treated with water (50 mL) andextracted with EtOAc (2×100 mL). The combined organic phase was washedwith brine (100 mL), dried over Na₂SO₄, filtered, concentrated to giveS3 (4.80 g, 48%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 3.89-3.86 (m, 4H), 2.63-2.55 (m, 2H),2.44-2.33 (m, 1H), 2.07-1.56 (m, 8H), 1.50-1.05 (m, 11H), 1.05-0.93 (m,7H), 0.93-0.78 (m, 2H), 0.76 (s, 3H).

Step 3 (S4). To anhydrous ethanol (100 mL) was added Na (2.94 g, 128mmol) in five portions. The mixture was stirred at 25° C. for 2 hours.S3 (4.8 g, 12.8 mmol) in THF (50 mL) was added to the reaction mixtureand then was stirred at 60° C. for 5 hrs. After the reaction mixture wascooled to 0° C., the reaction mixture was quenched by addition of H₂O(100 mL). The aqueous phase was extracted with EtOAc (3×100 mL). Thecombined organic phase was washed with brine (2×100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give S4 (4.80 g, 89%) asa solid.

¹H NMR (400 MHz, CDCl₃) δ 4.06-3.85 (m, 3H), 3.76-3.65 (m, 1H),3.58-3.40 (m, 2H), 3.26-3.18 (m, 1H), 2.08-1.56 (m, 8H), 1.56-1.05 (m,21H), 1.05-0.78 (m, 5H), 0.73 (s, 3H).

Step 4 (Compound 81). To a solution of S4 (4.80 g, 11.4 mmol) inmethanol (50 mL) was added hydrogen chloride (22.8 mL, 1M in H₂O)dropwise at 25° C. The mixture was stirred at 25° C. for 10 min. Themixture was poured into water (50 mL). The aqueous phase was extractedwith EtOAc (3×100 mL). The combined organic phase was washed with brine(100 mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash silica gel chromatography (0˜30% of EtOAc in PE) togive impure product as a solid, which was repurified by silica gelchromatography to give Compound 81 (600 mg) as a light yellow oil, whichwas triturated with MeCN (10 mL) at 25° C. for 2 hours to give Compound81 (500 mg, 10%) as a light yellow oil.

The structure of Compound 81 was confirmed by NOE.

¹H NMR (400 MHz, CDCl₃) δ 3.58-3.49 (q, J=6.8 Hz, J=14 Hz, 2H),3.47-3.36 (q, J=8.8 Hz, J=20.8 Hz, 2H), 2.72 (s, 1H), 2.57-2.48 (t,J=8.8 Hz, 1H), 2.18-2.13 (m, 1H), 2.10 (s, 3H), 2.04-1.78 (m, 3H),1.74-1.58 (m, 4H), 1.55-1.32 (m, 8H), 1.31-1.12 (m, 8H), 1.04-0.96 (m,1H), 0.93 (s, 3H), 0.58 (s, 3H).

LCMS Rt=1.113 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₄H₃₉02 [M+H−H₂O]⁺359, found 359.

Step 5 (S5). Liquid bromine (848 mg, 0.271 mL, 5.31 mmol) was addedslowly to a vigorously stirred aqueous sodium hydroxide solution (5.30mL, 4 M, 21.2 mmol) at 0° C. When all the bromine dissolved, the mixturewas diluted with cold (0° C.) dioxane (2 mL) and was added slowly to astirred solution of Compound 81 (200 mg, 0.531 mmol) in dioxane (2 mL)and water (1.5 mL). The homogeneous yellow solution became colorlessslowly and a white precipitate formed. The reaction mixture was stirredat 25° C. for another 16 hours. The remaining oxidizing reagent wasquenched with aqueous Na₂S₂O₃ (1.5 mL) and the mixture was then heatedat 80° C. until the solid material dissolved. Acidification of thesolution with aqueous hydrochloric acid (3 N) furnished a whiteprecipitate. The solid was filtered and washed with water (3×20 mL) togive a solid, which was dried in vacuo to give S5 (380 mg, crude) as anoil.

¹H NMR (400 MHz, CDCl₃) δ 3.58-3.50 (m, 2H), 3.46-3.38 (m, 2H),2.42-2.34 (m, 1H), 2.04 (s, 1H), 1.96-1.30 (m, 14H), 1.26-1.10 (m, 11H),1.03-0.90 (m, 4H), 0.71 (s, 3H).

Step 6 (Compound 82). To a solution of S5 (200 mg, 0.528 mmol) in DCM (3mL) was added HATU (301 mg, 0.792 mmol) and Et₃N (266 mg, 2.63 mmol) at25° C. After stirring at 25° C. for 10 min, N-methyl-1-phenylmethanamine(95.9 mg, 0.792 mmol) was added to the reaction mixture at 25° C. Thereaction mixture was stirred at 25° C. for 1.5 hours and quenched withice-water (10 mL). The aqueous phase was extracted with EtOAc (3×20 mL).The combined organic phase was washed with saturated brine (2×10 mL),dried over anhydrous Na₂SO₄, filtered and concentrated and the resultingresidue was purified by flash silica gel chromatography (0˜25% of EtOAcin PE) to give Compound 82 (100 mg) as a solid. Compound 82 wasredissolved in EtOAc (20 mL) and washed with H₂O (3×20 mL), dried overNa₂SO₄, filtered, concentrated in vacuo to give Compound 82 (78 mg, 31%)as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.38-7.29 (m, 2H), 7.25-7.21 (m, 2H),7.16-7.09 (m, 1H), 5.08-4.88 (m, 1H), 4.37-4.22 (m, 1H), 3.58-3.49 (m,2H), 3.47-3.33 (m, 2H), 2.99-2.91 (m, 3H), 2.88-2.64 (m, 2H), 2.38-2.26(m, 1H), 1.98-1.66 (m, 6H), 1.52-0.98 (m, 17H), 1.04-0.96 (m, 1H), 0.94(s, 3H), 0.78 (s, 3H).

LCMS Rt=1.172 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₃₁H₄₈NO₃ [M+H]⁺ 482, found 482.

Example 73. Synthesis of Compound 83

The synthesis of T1 is disclosed in WO2015/180679.

Step 1 (Compound 83). To a solution of DIPEA (37.8 mg, 0.293 mmol) inDMF (3 mL) was added N-methylaniline (48.4 mg, 0.452 mmol) at 25° C.under N₂. After stirring at 25° C. for 30 min, T1 (100 mg, 226 mmol) wasadded. The mixture was stirred at 50° C. for 16 hours and concentratedto give a light yellow oil, which was purified by HPLC (Column:YMC-Actus Triart C18 100*30 mm*5 um; Conditions: water (0.05% HCl)-ACN;Gradient 80%-100% B; Gradient Time (min): 9.5) to afford Compound 83(32.0 mg, 30%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.25-7.18 (m, 2H), 6.75-6.68 (m, 1H),6.62-6.59 (m, 2H), 4.11-3.98 (m, 2H), 3.58-3.38 (m, 4H), 3.00 (s, 3H),2.72 (brs, 1H), 2.62-2.56 (m, 1H), 2.22-2.05 (m, 1H), 2.00-1.92 (m, 1H),1.85-1.53 (m, 7H), 1.53-1.33 (m, 7H), 1.33-1.02 (m, 10H), 0.67 (s, 3H).

LCMS Rt=1.031 min in 1.5 min chromatography, 5-95 AB, purity 100%, MSESI calcd. for C₃₀H₄₆NO₃ [M+H]⁺ 468, found 468.

Example 74. Synthesis of Compound 84

Step 1 (Compound 84). To a solution of DIPEA (37.8 mg, 293 μmol) in DMF(3 mL) was added aniline (42.0 mg, 452 μmol) at 25° C. under N₂. Afterstirring at 25° C. for 30 min. T1 (100 mg, 0.226 mmol) was added. Themixture was stirred at 50° C. for 16 hours and concentrated to give alight yellow oil, which was purified by HPLC (Column: YMC-Actus TriartC18 100*30 mm*5 um; Conditions: water(0.05% HCl)-ACN; Gradient 75%-100%B; Gradient Time (min): 8) to afford Compound 84 (22.0 mg, 21%) as asolid.

¹H NMR (400 MHz, CDCl₃) δ 7.25-7.13 (m, 2H), 6.75-6.68 (m, 1H),6.62-6.53 (m, 2H), 4.69 (brs, 1H), 4.00-3.85 (m, 2H), 3.58-3.35 (m, 4H),2.73 (s, 1H), 2.62-2.53 (m, 1H), 2.28-2.15 (m, 1H), 1.98-1.90 (m, 1H),1.85-1.53 (m, 7H), 1.53-1.31 (m, 7H), 1.31-0.98 (m, 10H). 0.84 (s, 3H).

LCMS Rt=0.989 min in 1.5 min chromatography, 5-95 AB, purity 100%, MSESI calcd. for C₂₉H₄₄NO₃ [M+H]⁺ 454, found 454.

Example 75. Synthesis of Compound 85

Step 1 (Compound 85). To a solution of T2 (50 mg, 0.113 mmol) in DMF (5mL) was added N-methylaniline (14.4 mg, 0.135 mmol) and TEA (34.3 mg,0.339 mmol) at 25° C. under N₂. The mixture was stirred at 25° C. for 18h to give a yellow solution. The solution was poured into saturatedaqueous LiCl (20 mL) and extracted with EtOAc (3×30 mL). The combinedorganic phase was washed with saturated brine (2×30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give a light solid. Thesolid was purified by HPLC (Column:Xtimate C18 150*25 mm*5 um;Conditions: water (0.05% HCl)-ACN; Gradient 70%-100% B; Gradient Time(min): 10) to afford Compound 85 (31.0 mg, 59%) as a light solid.

¹H NMR (400 MHz, CDCl₃) δ 7.25-7.13 (m, 2H), 6.74-6.65 (m, 1H),6.59-6.54 (m, 2H), 4.10-3.95 (m, 2H), 3.55-3.45 (m, 2H), 3.22 (s, 2H),3.00 (s, 3H), 2.65-2.54 (m, 1H), 2.30-1.50 (m, 8H), 1.50-1.05 (m, 14H),1.05-0.70 (m, 3H), 0.70-0.65 (m, 5H).

LCMS Rt=1.029 min in 1.5 min chromatography, 5-95 AB, purity 100%, MSESI calcd. for C₃₀H₄₆NO₃ [M+H]⁺ 468, found 468.

Example 76. Synthesis of Compound 86

Step 1 (Compound 86). To a solution of T2 (50 mg, 0.113 mmol) in DMF (5mL) was added aniline (12.5 mg, 0.135 mmol) and TEA (34.3 mg, 0.339mmol) at 25° C. under N₂. The mixture was stirred at 25° C. for 18 h togive a yellow solution. The mixture was poured into saturated aqueousLiCl (50 mL) and extracted with EtOAc (3×30 mL). The combined organicphase was washed with saturated brine (2×50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give a light solid, which waspurified by HPLC (Column:Xtimate C18 150*25 mm*5 um; Conditions:water(0.05% HCl)-ACN; Gradient 70%-100% B; Gradient Time (min): 10) toafford Compound 86 (7.00 mg, 14%) as a light solid.

¹H NMR (400 MHz, CDCl₃) δ 7.25-7.10 (m, 2H), 6.74-6.65 (m, 1H),6.59-6.52 (m, 2H), 4.68-4.63 (m, 1H), 4.02-3.82 (m, 2H), 3.55-3.42 (m,2H), 3.21 (s, 2H), 2.62-2.52 (m, 1H), 2.30-2.15 (m, 1H), 2.10-2.05 (m,1H), 1.98-1.50 (m, 7H), 1.50-0.92 (m, 15H), 0.90-0.65 (m, 3H), 0.65 (s,3H).

LCMS Rt=1.019 min in 2.0 min chromatography, 5-95 AB, purity 100%, MSESI calcd. for C₂₉H₄₄NO₃ [M+H]⁺ 454, found 454.

Example 77. Synthesis of Compound 87 and Compound 88

Step 1 (U2). To a solution of commercially availabledehydroisoandrosterone U1 (47 g, 162 mmol) in MeOH (200 mL) and THF (200mL) was added Pd/C (5 g, <1% water) and the solution was hydrogenatedunder 30 psi of hydrogen at 25° C. for 48 hrs. The mixture was filteredthrough a pad of celite and the filtrate was concentrated in vacuo togive U2 (45 g, 91%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 3.65-3.54 (m, 1H), 2.49-2.38 (m, 1H),2.13-1.99 (m, 1H), 1.97-1.88 (m, 1H), 1.87-1.76 (m, 3H), 1.74-1.63 (m,2H), 1.59-1.07 (m, 12H), 1.03-0.94 (m, 2H), 0.89-0.79 (m, 6H), 0.74-0.63(m, 1H).

Step 2 (U3). To a solution of U2 (160 g, 550 mmol) and silica gel (300g) in DCM (2 L) was added PCC (237 g, 1100 mmol) at 25° C. The mixturewas stirred for 1 hr. The solution was filtered and the filter cake waswashed with DCM (500 mL). The filtrate was diluted with PE (2 L) andstirred with silica gel (100 g) for 30 min. The silica gel was filteredoff and washed with DCM (300 mL). The combined filtrate was concentratedin vacuo to give U3 (150 g, crude) as a solid.

¹H NMR (CDCl₃, 400 MHz) δ 2.50-2.20 (m, 4H), 2.25-1.90 (m, 4H),1.85-1.80 (m, 2H), 1.75-1.65 (m, 1H), 1.60-1.45 (m, 3H), 1.45-1.20 (m,6H), 1.05-0.90 (m, 4H), 0.89-0.75 (m, 4H).

Step 3 (U4). A suspension of LiCl (6.14 g, 145 mmol, anhydrous) in THF(600 mL, anhydrous) was stirred at 10° C. for 30 mins under N₂. FeCl₃(12.3 g, 76.2 mmol, anhydrous) was added at 10° C. The mixture wascooled to −30° C. To the mixture was added MeMgBr (92.3 mL, 3M indiethyl ether) dropwise at −30° C. The mixture was stirred at −30° C.for 10 mins. U3 (20 g, 69.3 mmol) was added at −30° C. The mixture wasstirred at −15° C. for 2 hours. To the mixture was added citric acid(400 mL, 10% aq.). The mixture was extracted with EtOAc (3×200 mL). Thecombined organic phase was washed with saturated brine (300 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to give crudeproduct which was purified by silica gel chromatography(PE/EtOAc=1/101/5) to give U4 (18.5 g, 88%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 2.45-2.39 (m, 1H), 2.12-2.00 (m, 1H),1.98-1.88 (m, 1H), 1.84-1.74 (m, 2H), 1.72-1.64 (m, 1H), 1.61-1.42 (m,7H), 1.33-1.22 (m, 8H), 1.20 (s, 3H), 1.08-0.95 (m, 1H), 0.86 (s, 3H),0.84-0.79 (m, 1H), 0.77 (s, 3H)

Step 5 (Compound 87). To a solution of aniline (61 mg, 0.656 mmol) inDCE (2 mL) was added U4 (100 mg, 0.328 mmol) and HOAc (39.3 mg, 0.656mmol). The mixture was stirred at 15° C. for 10 minutes. Then NaBH(OAc)₃(127 mg, 0.656 mmol) was added. The reaction mixture was stirred at 15°C. for 16 hrs. The mixture was quenched with sat. aqueous NaHCO₃ (20 mL)and extracted with DCM (3×10 mL). The combined organic phase was driedover Na₂SO₄, filtered, concentrated and purified by silica gelchromatography (0-10% of EtOAc in (PE and NH₃/H₂O, v:v=100:1) to giveimpure Compound 87 (20 mg) as a solid, which was triturated with hexane(3 mL). The mixture was filtered and the filter cake was washed withhexane (3×1 mL) to give pure Compound 87 (12 mg, 10%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.17-7.07 (m, 2H), 6.66-6.58 (m, 3H),3.64-3.52 (m, 1H), 3.46-3.31 (m, 1H), 2.29-2.15 (m, 1H), 1.81-1.58 (m,4H), 1.53-1.36 (m, 6H), 1.35-1.23 (m, 5H), 1.21-1.07 (m, 8H), 1.00-0.89(m, 1H), 0.82-0.72 (m, 7H).

LCMS Rt=0.918 min in 2.0 min chromatography, 30-90 AB, purity 100%, MSESI calcd. for C₂₆H₄₀NO [M+H]⁺ 382, found 382.

Step 6 (Compound 88). To a solution of Compound 87 (500 mg, 1.31 mmol inTHF (10 mL) was added acetic acid (157 mg, 2.62 mmol) andparaformaldehyde (486 mg, 5.24 mmol). After stirring at 25° C. for 2.5hrs, sodium cyanoborohydride (205 mg, 3.27 mmol) was added. The reactionmixture was stirred at 25° C. for 16 hrs and quenched with water (30mL), extracted with EtOAc (2×30 mL). The organic layers were washed withbrine (2×40 mL), dried over Na₂SO₄, filtered, concentrated in vacuo togive a residue, which was purified by silica gel chromatography(PE/EtOAc=10/1 to 4/1) to afford Compound 88 (37 mg, 12%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.23-7.17 (m, 2H), 6.91-6.85 (m, 1H),6.74-6.67 (m, 2H), 3.76-3.67 (m, 1H), 2.88-2.80 (m, 3H), 2.02-1.62 (m,5H), 1.62-1.56 (m, 1H), 1.53-1.43 (m, 4H), 1.42-1.31 (m, 2H), 1.31-1.22(m, 6H), 1.21-1.16 (m, 5H), 1.15-1.04 (m, 1H), 1.03-0.86 (m, 1H),0.83-0.77 (m, 4H), 0.75 (s, 3H).

LCMS Rt=0.734 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. For C₂₇H₄₂NO [M+H]⁺ 396, found 396.

Example 78. Synthesis of Compound 89

The synthesis of U4 is disclosed in WO2016/61527.

Step 1 (Compound 89). To a solution of U4 (200 mg, 0.656 mmol) intoluene (3 mL) was added 4-fluoroaniline (145 mg, 1.31 mmol) and4-methylbenzenesulfonic acid (112 mg, 0.656 mmol) at 15° C. under N₂.The mixture was refluxed at 110° C. for 16 hrs. After cooling to 15° C.,NaBH₄ (49.5 mg, 1.31 mmol) was added. The mixture was poured into water(15 mL) and extracted with DCM (2×20 mL). The combined organic layerswere washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by flash silicagel chromatography (0˜15% of EtOAc in PE) to give Compound 89 (11 mg,4%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 6.87-6.79 (m, 2H), 6.60-6.50 (m, 2H),3.49-3.37 (m, 1H), 3.36-3.25 (m, 1H), 2.28-2.11 (m, 1H), 1.75-1.62 (m,3H), 1.60-1.55 (m, 1H), 1.54-1.44 (m, 4H), 1.43-1.32 (m, 2H), 1.31-1.22(m, 5H), 1.21-1.14 (m, 7H), 1.14-1.06 (m, 1H), 1.03-0.86 (m, 1H),0.84-0.69 (m, 7H).

LCMS Rt=1.066 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. For C₂₆H₃₉FNO [M+H]⁺ 400, found 400.

Example 79. Synthesis of Compound 90

Step 1. (Compound 90). A solution of U4 (200 mg, 0.656 mmol),3-fluoroaniline (109 mg, 0.984 mmol), 4-methylbenzenesulfonic acid (56.4mg, 0.328 mmol) in toluene (5 mL) was stirred at 110° C. for 12 hrs.After cooling to 25° C., NaBH₄ (49.5 mg, 1.31 mmol) and 5 mL of MeOH wasadded. The mixture was stirred at 25° C. for 30 mins, poured into water(20 mL) and extracted with DCM (2×20 mL). The combined organic layerswere washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by HPLC (column:Phenomenex Synergi C18 150*30 mm*4 um, gradient: 95-95% B (A=0.05%HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) to give Compound 90 (16mg, 6%) as a solid.

The structure was assigned based on a similar reductive amination in theliterature (Steroids, 2011, 1098-1102).

¹H NMR (400 MHz, CDCl₃) δ 7.06-7.00 (m, 1H), 6.38-6.28 (m, 3H),3.74-3.67 (m, 1H), 3.37-3.30 (m, 1H), 2.26-2.16 (m, 1H), 1.77-1.63 (m,3H), 1.62-1.57 (m, 2H), 1.54-1.34 (m, 7H), 1.32-1.08 (m, 11H), 1.04-0.85(m, 2H), 0.83-0.74 (m, 6H).

LCMS Rt=1.309 min in 2.0 min chromatography, 30-90 AB, purity 96.5%, MSESI calcd. For C₂₆H₃₉FNO [M+H]⁺ 400, found 400.

Example 80. Synthesis of Compound 91

Step 1 (Compound 91). A solution of U4 (200 mg, 0.656 mmol),2-fluoroaniline (109 mg, 0.984 mmol), 4-methylbenzenesulfonic acid (56.4mg, 0.328 mmol) in toluene (5 mL) was stirred at 110° C. for 12 hrs.After cooling to 25° C., NaBH₄ (49.5 mg, 1.31 mmol) and 5 mL of MeOH wasadded. The mixture was stirred at 25° C. for 30 mins, poured into water(30 mL) and extracted with DCM (2×20 mL). The combined organic layerswere washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by HPLC (column:Phenomenex Synergi C18 150*30 mm*4 um, gradient: 93-93% B (A=0.05%HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) to give Compound 91 (6mg, 2%) as a solid.

The structure was assigned based on a similar reductive amination in theliterature (Steroids, 2011, 1098-1102).

¹H NMR (400 MHz, CDCl₃) δ 6.95-6.90 (m, 2H), 6.79-6.74 (m, 1H),6.56-6.52 (m, 1H), 3.85-3.81 (m, 1H), 3.42-3.35 (m, 1H), 2.27-2.17 (m,1H), 1.76-1.64 (m, 2H), 1.62-1.32 (m, 10H), 1.30-1.06 (m, 11H),1.05-0.86 (m, 2H), 0.83-0.66 (m, 6H).

LCMS Rt=1.393 min in 2.0 min chromatography, 30-90 AB, purity 100%, MSESI calcd. For C₂₆H₃₉FNO [M+H]⁺ 400, found 400.

Example 81. Synthesis of Compound 92, Compound 93 and Compound 94

Step 1 (Compound 92) A solution of U4 (3 g, 9.85 mmol),phenylmethanamine (4.22 g, 39.4 mmol), NaBH(OAc)₃ (5.21 g, 24.6 mmol),HOAc (2.36 g, 39.4 mmol) in 1, 2-dichloroethane (30 mL) was stirred at25° C. for 12 hrs. Saturated Na₂CO₃ (10 mL) was added to the mixture andstirred for 10 mins. The mixture was poured into water (20 mL) andextracted with DCM (2×100 mL). The combined organic layers were washedwith brine (200 mL), dried over Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by column chromatography on silicagel (PE/EtOAc=1:1) to give Compound 92 (2.3 g, 59%) as a solid. Compound92 (100 mg, 0.252 mmol) was repurified by prep-HPLC (column: Gemini150*25 5 u, gradient: 85-100%, Conditions: water (10 mM NH₄HCO₃)-ACN,flow rate: 30 mL/min) to give Compound 92 (13 mg, 13%) as a solid.

The structure was assigned based on a similar reductive amination in theliterature (Steroids, 2011, 1098-1102).

¹H NMR (400 MHz, CDCl₃) δ 7.41-7.39 (m, 2H), 7.33 (t, J=8 Hz, 2H),7.28-7.24 (m, 1H), 3.99-3.81 (m, 2H), 2.58 (m, 1H), 2.02-1.91 (m, 2H),1.66-1.48 (m, 5H), 1.46-1.10 (m, 15H), 1.07-0.82 (m, 7H), 0.77-0.68 (m,4H).

LCMS Rt=0.783 min in 2.0 min chromatography, 30-90 AB, purity 100%, MSESI calcd. For C₂₇H₄₂NO [M+H]⁺ 396, found 396.

Step 2 (Compound 93). To a solution of Compound 92 (2.3 g, 5.81 mmol) inMeOH (30 mL) was added Pd/C (0.5 g, <1% water). Then the solution washydrogenated under 50 psi of hydrogen at 25° C. for 3 h. The mixture wasfiltered through a pad of celite and the filtrate was concentrated invacuo to afford Compound 93 (1.5 g, 85%) as a solid. Compound 93 (100mg, 0.327 mmol) was purified by silica gel chromatography(DCM/MeOH=10/1) to give Compound 93 (14 mg, 14%) as a solid. as a solid.

¹H NMR (400 MHz, CDCl₃) δ 2.67-2.62 (m, 1H), 2.04-1.95 (m, 1H),1.72-1.64 (m, 2H), 1.62-1.60 (m, 1H), 1.56-1.46 (m, 4H), 1.40-1.09 (m,16H), 1.01-0.85 (m, 3H), 0.79-0.71 (m, 4H), 0.62 (s, 3H).

LCMS Rt=4.746 min in 7.0 min chromatography, 30-90 CD, purity 100%, MSESI calcd. For C₂₀H₃₆NO [M+H]⁺ 306, found 306.

Step 3 (Compound 94). To a solution of Compound 93 (200 mg, 0.65 mmol)and TEA (164 mg, 1.63 mmol) in DCM (2 mL) was added benzoyl chloride(182 mg, 1.3 mmol) at 25° C. The reaction mixture was stirred at 25° C.for 15 hrs under N₂. The reaction mixture was quenched with a saturatedaqueous NH₄Cl (20 mL) solution and extracted with DCM (20 mL×2). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by silica gel column (EtOAc/PE=3/1) to give Compound 94 (120mg, 45%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.76-7.74 (m, 2H), 7.52-7.47 (m, 1H),7.45-7.41 (m, 2H), 5.95-5.92 (m, 1H), 4.14-4.07 (m, 1H), 2.26-2.18 (m,1H), 1.78-1.66 (m, 3H), 1.63-1.58 (m, 1H), 1.53-1.23 (m, 13H), 1.2-1.16(m, 5H), 1.02-0.92 (m, 2H), 0.87-0.76 (m, 7H).

LCMS Rt=1.355 min in 2.0 min chromatography, 30-90 AB, purity 100%, MSESI calcd. for C₂₇H₄₁NO₂ [M+H]⁺ 410, found 410.

Example 82. Synthesis of Compound 95

Step 1 (Compound 95). To a solution of Compound 93 (200 mg, 0.65 mmol)and DMAP (198 mg, 1.63 mmol) in DCM (3 mL) was added acetic anhydride(132 mg, 1.3 mmol) at 25° C. The mixture was stirred at 25° C. for 1 hr.The mixture was poured into water (10 mL) and extracted with DCM (2×10mL). The combined organic layers were washed with brine (30 mL), driedover Na₂SO₄, filtered and concentrated. The residue was purified bysilica gel chromatography (PE/EtOAc=3/1) to give Compound 95 (60 mg, 26%yield) as a solid.

The structure was assigned based on a similar reductive amination in theliterature (Steroids, 2011, 1098-1102).

¹H NMR (400 MHz, CDCl₃) δ 5.25-5.23 (m, 1H), 3.91-3.84 (m, 1H),2.15-2.07 (m, 1H), 1.97 (s, 3H), 1.71-1.62 (m, 3H), 1.54-1.44 (m, 4H),1.42-1.04 (m, 16H), 0.99-0.88 (m, 1H), 0.81-0.73 (m, 4H), 0.67 (s, 3H).

LCMS Rt=0.869 min in 2 min chromatography, 30-90 AB, purity 100%, MS ESIcalcd. For C₂₂H₃₈NO₂ [M+H]⁺ 348, found 348.

Example 83. Synthesis of Compound 96

Step 1 (Compound 96). To a solution of Compound 93 (200 mg, 0.65 mmol)and TEA (164 mg, 1.63 mmol) in DCM (3 mL) was added benzenesulfonylchloride (229 mg, 1.3 mmol) at 0° C. The mixture was stirred at 25° C.for 1 hr. The mixture was poured into water (10 mL) and extracted withDCM (2×20 mL). The combined organic layer was washed with brine (30 mL),dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash column (PE/EtOAc=5/1˜3/1) to give V1 (80 mg, 40%) as a solid.

The structure was assigned based on a similar reductive amination in theliterature (Steroids, 2011, 1098-1102).

¹H NMR (400 MHz, CDCl₃) δ 7.88-7.86 (m, 2H), 7.58-7.48 (m, 3H),4.37-4.34 (m, 1H), 3.09-3.06 (m, 1H), 1.85-1.72 (m, 1H), 1.63-1.39 (m,11H), 1.38-1.33 (m, 1H), 1.23-1.15 (m, 8H), 0.95-0.75 (m, 6H), 0.72 (s,3H), 0.65 (s, 3H).

LCMS Rt=1.251 min in 2.0 min chromatography, 30-90 AB, purity 100%, MSESI calcd. for C₂₆H₄₀NO₃S [M+H]⁺ 446, found 446.

Step 2 (Compound 96). To a solution of V1 (40 mg, 0.090 mmol) and Cs₂CO₃(58.3 mg, 0.179 mmol) in DMF (2 mL) was added iodomethane (19 mg, 0.134mmol) at 25° C. The mixture was stirred at 25° C. for 16 hr. The mixturewas poured into water (10 mL) and extracted with EtOAc (2×20 mL). Thecombined organic layers were washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated.

The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to3/1) to give Compound 96 (32 mg, 78%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.80-7.78 (m, 2H), 7.57-7.48 (m, 3H),3.75-3.70 (m, 1H), 2.78 (s, 3H), 1.91-1.89 (m, 1H), 1.66-1.53 (m, 4H),1.51-1.43 (m, 3H), 1.39-1.09 (m, 15H), 1.02-0.86 (m, 2H), 0.79-0.74 (m,7H).

LCMS Rt=1.221 min in 2.0 min chromatography, 30-90 AB, purity 98.5%, MSESI calcd. For C₂₇H₄₀NO₂S [M−H₂O+H]⁺442, found 442.

Example 84. Synthesis of Compound 97 and Compound 98

Step 1 (Compound 97). To a solution of Compound 93 (100 mg, 0.327 mmol)and DIEA (105 mg, 0.817 mmol) in DCM (2 mL) was added methanesulfonylchloride (74.9 mg, 0.654 mmol) at 0° C. The mixture was stirred at 25°C. for 1 hr. The mixture was poured into water (10 mL) and extractedwith DCM (2×10 mL). The combined organic layers were washed with brine(30 mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash silica gel chromatography (PE/EtOAc=2/1) to giveCompound 97 (50 mg, 40%) as a solid.

The structure was assigned based on a similar reductive amination in theliterature (Steroids, 2011, 1098-1102).

¹H NMR (400 MHz, CDCl₃) δ 4.13-4.11 (m, 1H), 3.28-3.21 (m, 1H), 2.95 (s,3H), 2.22-2.12 (m, 1H), 1.83-1.78 (m, 1H), 1.70-1.59 (m, 3H), 1.55-1.35(m, 7H), 1.29-1.09 (m, 11H), 1.05-0.87 (m, 2H), 0.81-0.73 (4H), 0.69 (s,3H).

LCMS Rt=0.869 min in 2.0 min chromatography, 30-90 AB, purity 98.8%, MSESI calcd. For C₂₁H₃₆NO₂S [M−H₂O+H]⁺366, found 366.

Step 2 (Compound 98). To a solution of Compound 97 (40 mg, 0.90 mmol)and Cs₂CO₃ (84.7 mg, 260 umol) in DMF (2 mL) was added iodomethane (29.5mg, 0.208 mmol) at 25° C. After stirring at 25° C. for 16 hr, themixture was poured into water (10 mL) and filtered. The filter cake wasconcentrated to give Compound 98 (35 mg, 85%) as a solid.

The structure was assigned based on a similar reductive amination in theliterature (Steroids, 2011, 1098-1102).

¹H NMR (400 MHz, CDCl₃) δ 3.65-3.60 (m, 1H), 2.87 (s, 3H), 2.77 (s, 3H),1.92-1.81 (m, 2H), 1.75-1.57 (m, 4H), 1.53-1.43 (m, 4H), 1.36-1.12 (m,13H), 1.06-0.89 (m, 2H), 0.77-0.73 (m, 7H).

MS ESI calcd. For C₂₂H₄₀NO₃S [M+H]⁺ 398, found 398.

Example 85. Synthesis of Compound 99

Step 1 (U5). A solution of U4 (3 g, 9.85 mmol),N-methyl-1-phenylmethanamine (4.77 g, 39.4 mmol), NaBH(OAc)₃ (5.21 g,24.6 mmol) and HOAc (2.36 g, 39.4 mmol) in 1, 2-dichloroethane (30 mL)was stirred at 60° C. for 12 hrs. Then saturated aqueous Na₂CO₃ (10 mL)was added to the mixture and the mixture was stirred for 10 mins. Themixture was poured into water (20 mL) and extracted with DCM (2×100 mL).The combined organic layers were washed with brine (200 mL), dried overNa₂SO₄ and filtered concentrated in vacuo. The crude product waspurified by column chromatography on silica gel (PE/EtOAc=1/1) to giveU5 (0.5 g, 12%) as a solid.

The structure was assigned based on a similar reductive amination in theliterature (Steroids, 2011, 1098-1102).

¹H NMR (400 MHz, CDCl₃) δ 7.34-7.28 (m, 4H), 7.23-7.20 (m, 1H),3.64-3.36 (m, 2H), 2.18-2.14 (m, 1H), 2.08-2.02 (m, 4H), 1.98-1.89 (m,1H), 1.69-1.61 (m, 2H), 1.56-1.34 (m, 7H), 1.32-1.04 (m, 12H), 0.98-0.86(m, 5H), 0.78-0.71 (m, 4H).

Step 2 (U6). To a solution of U5 (500 mg, 1.22 mmol) in THF/MeOH (10 mL,1/1) was added Pd/C (0.5 g, water <1%) at 25° C. The solution washydrogenated under 50 psi of hydrogen at 25° C. for 16 hrs. The mixturewas filtered through a pad of celite and the filtrate was concentratedin vacuo to afford U6 (300 mg, 60%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 2.45-2.43 (m, 4H), 2.02-1.99 (m, 1H),1.82-1.80 (m, 1H), 1.68-1.64 (m, 1H), 1.63-1.43 (m, 9H), 1.60-1.36 (m,6H), 1.35-1.11 (m, 5H), 1.03-0.82 (m, 3H), 0.77-0.74 (m, 4H), 0.69 (s,3H).

Step 3 (Compound 99). To a solution of U6 (100 mg, 0.31 mmol) and TEA(69.2 mg, 0.69 mmol) in DCM (3 mL) was added methyl chloroformate (58.9mg, 0.62 mmol) at 0° C. The mixture was stirred at 25° C. for 1 hr. Themixture was poured into water (10 mL) and extracted with DCM (2×20 mL).The combined organic layers were washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated. The residue was purified by silicagel chromatography (PE/EtOAc=5/1˜3/1) to give Compound 99 (27 mg, 23%)as a solid.

¹H NMR (400 MHz, CDCl₃) δ 4.07-3.95 (m, 1H), 3.68 (s, 3H), 2.86 (s, 3H),1.90-1.31 (m, 1H), 1.77-1.63 (m, 4H), 1.53-1.43 (m, 4H), 1.39-1.15 (m,13H), 1.10-0.81 (m, 3H), 0.79-0.73 (m, 4H), 0.69 (s, 3H).

LCMS Rt=1.259 min in 2.0 min chromatography, 30-90 AB, purity 99.3%, MSESI calcd. For C₂₃H₄₁NO₃ [M+H]⁺ 378, found 378.

Example 86. Synthesis of Compound 100

The synthesis of W1 is disclosed in WO2014/169833.

Step 1 (Compound 100). To a solution of W1 (0.24 g, 0.83 mmol) in THF(10 mL) was added PhLi (11 mL, 1.5 M in ether, 16.5 mmol). The mixturewas stirred at 65° C. for 4 h. After cooling, NH₄Cl (10 mL, sat.) wasadded. The mixture was extracted with EtOAc (20 mL). The organic layerwas separated, dried over Na₂SO₄, filtered and concentrated in vacuo,purified by silica gel chromatography (PE/EtOAc=6/1 to 5/1) to giveCompound 100 (120 mg) as a light brown oil. The crude was dissolved inMeCN (20 mL) and water (5 mL) was added. The mixture was concentrated invacuo to yield a brown oil. The residue was dissolved in DCM (3 mL) andconcentrated in vacuo to give Compound 100 (83 mg, 27%) as a lightsolid.

¹H NMR (400 MHz, CDCl₃) δ 7.40-7.28 (m, 5H), 2.47-2.32 (m, 1H),2.18-2.05 (m, 1H), 1.86 (brs, 1H), 1.80-1.60 (m, 5H), 1.53-1.41 (m, 5H),1.34-1.20 (m, 10H), 1.13-0.92 (m, 7H), 0.48-0.37 (m, 1H).

LCMS Rt=0.975 min in 2.0 min chromatography, 30-90AB, purity 98.2%, MSESI calcd. for C₂₅H₃₃ [M+H−2H₂O]⁺ 333, found 333.

Example 87. Synthesis of Compound 101

Step 1 (W2). To a solution of W1 (5 g, 17.2 mmol) and 2,6-dimethylpyridine (4.59 g, 42.9 mmol) in DCM (100 mL) was addeddrop-wise tert-butyldimethylsilyl trifluoromethanesulfonate (9.09 g,34.4 mmol) at 0° C. After stirring at 25° C. for 16 hrs, the reactionmixture was quenched with water (100 mL) and extracted with EtOAc (2×100mL). The combined organic phase washed with brine (100 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel chromatography (100-200 mesh silica gel, PE/EtOAc=10/1) toafford W2 (6 g, 86%) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 2.50-2.40 (m, 1H), 2.16-2.05 (m, 1H),1.96-1.90 (m, 1H), 1.82-1.70 (m, 4H), 1.70-0.95 (m, 18H), 0.95-0.60 (m,1H), 0.95-0.75 (m, 12H), 0.07 (s, 6H).

Step 2 (W3). To KHMDS (9.88 mL, 1M in THF) was added a solution of W2 (2g, 4.94 mmol) in THF (10 mL) at 0° C. After warming to 20° C. andstirring at 20° C. for 30 mins, a solution of1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(2.64 g, 7.41 mmol) in THF (15 mL) was added at 0° C. The mixture waswarmed to 20° C. and stirred at 20° C. for 17 hours. Then the mixturewas quenched with water (20 mL) and extracted with EtOAc (2×20 mL). Thecombined organic phase was washed with brine (2×30 mL), dried overNa₂SO₄, filtered, concentrated in vacuo to give a crude product, whichwas purified by flash silica gel chromatography (0-10% of EtOAc in PE,60 mins) to give W3 (1.47 g, 56%) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 5.56 (s, 1H), 2.25-2.17 (m, 1H), 2.01-1.95 (m,1H), 1.82-1.60 (m, 7H), 1.55-1.05 (m, 15H), 0.96 (s, 3H), 0.90-0.80 (m,9H), 0.08 (s, 6H).

Step 3 (W4). To a mixture of W3 (200 mg, 0.372 mmol), phenylboronic acid(58.8 mg, 0.48 mmol) and Pd(dppf)Cl₂ (28.3 mg, 0.0372 mmol) in THF (4mL), NaOH (0.24 mL, 2 M in water) was added. The mixture was degassedunder vacuum and purged with N₂. The reaction mixture was stirred at 80°C. for 1 hour. The reaction mixture was quenched with sat. aqueousNaHCO₃ (3 mL) and extracted with EtOAc (2×10 mL). The combined organiclayers were washed with brine (10 mL), dried over Na₂SO₄, filtered, andconcentrated. The crude product was purified by flash silica gelchromatography (0% to 5% of EtOAc in PE) to give W4 (232 mg, crude) asan oil.

¹H NMR (400 MHz, CDCl₃) δ 7.45-7.38 (m, 2H), 7.35-7.28 (m, 1H),7.25-7.20 (m, 2H), 5.91-5.87 (m, 1H), 2.28-2.19 (m, 1H), 2.10-1.95 (m,2H), 1.89-1.62 (m, 7H), 1.59-1.48 (m, 4H), 1.48-1.37 (m, 5H), 1.37-1.18(m, 6H), 1.02 (s, 3H), 1.02-0.70 (m, 8H), 0.07 (s, 6H).

Step 5 (W5). To a mixture of W4 (232 mg, 0.499 mmol) in THF (2 mL) wasadded TBAF (332 mg, 0.998 mmol) at 80° C. After stirring at 80° C. for18 h, the mixture was cooled to 15° C., treated with water (5 mL) andextracted with EtOAc (3×10 mL). The combined organic phase was washedwith brine (2×10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash silica gelchromatography (0˜10% of EtOAc in PE) to give W5 (160 mg, 94% yield for2 steps) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 7.40-7.35 (m, 2H), 7.35-7.25 (m, 1H),7.25-7.18 (m, 2H), 5.91-5.87 (m, 1H), 2.41-2.38 (m, 1H), 2.25-2.12 (m,1H), 2.11-1.95 (m, 2H), 1.95-1.81 (m, 3H), 1.80-1.61 (m, 3H), 1.61-1.52(m, 1H), 1.52-1.48 (s, 3H), 1.48-1.32 (m, 3H), 1.32-1.15 (m, 5H), 1.02(s, 3H), 0.92-0.82 (m, 3H).

Step 6 (Compound 101). To a solution of W5 (130 mg, 0.37 mmol) in EtOAc(15 mL) was added Pd/C (wet, 10%, 0.1 g) under N₂. The suspension wasdegassed under vacuum and purged with H₂ three times. The mixture wasstirred under H₂ (15 psi) at 15° C. for 0.5 hours to give a blacksuspension. The mixture was filtered and concentrated. The residue waspurified by flash silica gel chromatography (0˜10% of EtOAc in PE) togive Compound 101 (33 mg, 25%) as a solid.

The structure of Compound 101 was confirmed by X-ray crystallography.

¹H NMR (400 MHz, CDCl₃) δ 7.31-7.27 (m, 2H), 7.24-7.15 (m, 3H),2.81-2.75 (m, 1H), 2.12-2.03 (m, 1H), 2.01-1.91 (m, 1H), 1.91-1.78 (m,4H), 1.71-1.61 (m, 2H), 1.61-1.52 (m, 3H), 1.52-1.41 (m, 4H), 1.41-1.38(s, 2H), 1.38-1.21 (m, 6H), 1.21-1.09 (m, 2H), 1.05-0.79 (m, 2H), 0.46(s, 3H).

LCMS Rt=1.398 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₅H₃₅ [M+H−H₂O]⁺ 335, found 335.

Example 88. Synthesis of Compound 102

Step 1 (X1). To a mixture of W3 (200 mg, 0.372 mmol),p-methylphenylboronic acid (65.6 mg, 0.48 mmol) and Pd(dppf)Cl₂ (28.3mg, 0.0372 mmol) in THF (4 mL), NaOH (0.24 mL, 2 M in water) was added.The mixture was degassed under vacuum and purged with N₂. The reactionmixture was stirred at 80° C. for 1 hour. The reaction mixture wasquenched with sat. aqueous NaHCO₃ (3 mL) and extracted with EtOAc (2×5mL), the combined layers were washed with brine (10 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo. The product was purified byflash chromatography on silica (0% to 5% of EtOAc in PE) to give X1 (240mg, impure) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 7.30-7.25 (m, 2H), 7.12-7.08 (m, 2H),5.89-5.85 (m, 1H), 2.33 (s, 3H), 2.33-2.15 (m, 1H), 2.11-1.95 (m, 2H),1.90-1.61 (m, 6H), 1.61-1.58 (m, 1H), 1.53-1.46 (m, 3H), 1.46-1.41 (m,2H), 1.41-1.35 (m, 2H), 1.35-1.30 (m, 2H), 1.30-1.21 (m, 7H), 1.21-1.08(m, 1H), 1.01 (s, 3H), 0.90-0.81 (m, 6H), 0.07 (s, 6H).

Step 2 (X2). To a mixture of X1 (232 mg, 0.484 mmol) in THF (2 mL), TBAF(322 mg, 0.968 mmol) was added at 80° C. After stirring at 80° C. for 18h, the mixture was cooled to 15° C., treated with water (5 mL) andextracted with EtOAc (3×10 mL). The combined organic phase was washedwith saturated brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash silica gelchromatography (0˜10% of EtOAc in PE) to give X2 (100 mg, 56% yield for2 steps) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 7.32-7.25 (m, 2H), 7.12-7.08 (m, 2H),5.87-5.84 (m, 1H), 2.33 (s, 3H), 2.22-2.10 (m, 1H), 2.09-1.91 (m, 2H),1.91-1.81 (m, 3H), 1.79-1.55 (m, 4H), 1.55-1.40 (m, 5H), 1.40-1.12 (m,9H), 1.00 (s, 3H), 0.90-0.80 (m, 1H).

Step 3 (Compound 102). To a solution of X2 (100 mg, 0.274 mmol) in EtOAc(5 mL) was added Pd/C (wet, 10%, 0.1 g) under N₂. The suspension wasdegassed under vacuum and purged with H₂ three times. The mixture wasstirred under H₂ (15 psi) at 15° C. for 0.5 hours to give a blacksuspension. The mixture was filtered and concentrated. The residue waspurified by flash silica gel chromatography (0˜10% of EtOAc in PE) togive Compound 102 (17 mg, 17%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.12-7.05 (m, 4H), 2.69-2.60 (m, 1H), 2.32 (s,3H), 2.11-2.01 (m, 1H), 2.00-1.72 (m, 5H), 1.71-1.52 (m, 4H), 1.52-1.42(m, 3H), 1.42-1.32 (m, 4H), 1.32-1.15 (m, 7H), 1.15-0.90 (m, 3H), 0.46(s, 3H).

LCMS Rt=1.472 min in 2 min chromatography, 30-90AB, purity 98%, MS ESIcalcd. for C₂₆H₃₇ [M+H-H₂O]⁺349, found 349.

Example 89. Synthesis of Compound 103

Step 1 (Y1). To a mixture of W3 (200 mg, 0.372 mmol),pyridin-4-ylboronic acid (59.3 mg, 0.483 mmol) and NaOH (0.241 mL, 2 Min water) in THF (4 mL), Pd(dppf)Cl₂ (5 mg, 0.00656 mmol) was addedunder N₂. The suspension was stirred at 80° C. for 1 h and then wascooled to ambient temperature. The reaction mixture was quenched withsat.NaHCO₃ (3 mL). The mixture was extracted with EtOAc (2×5 mL). Thecombined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by flash chromatography on silica gel (0% to 5% of EtOAc in PE)to give Y1 (210 mg, impure) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 8.53-8.45 (d, 2H), 7.31-7.20 (d, 2H),6.20-6.10 (m, 1H), 2.32-2.20 (s, 1H), 2.12-1.98 (m, 2H), 1.87-1.59 (m,6H), 1.59-1.42 (m, 4H), 1.42-1.38 (m, 6H), 1.38-1.12 (m, 9H), 1.03 (s,3H), 0.91-0.81 (m, 5H), 0.06 (s, 6H).

Step 2 (Y2). To a mixture of Y1 (210 mg, impure) in THF (2 mL) was addedTBAF (328 mg, 0.985 mmol). The reaction solution was stirred at 80° C.for 18 hrs. Water (5 mL) was added. The mixture was extracted with EtOAc(2×10 mL). The combined organic layers were washed with brine (5 mL),dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash column (0˜30% of EtOAc in PE) to give Y2 (56 mg, 32% yield for2 steps) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.55-8.45 (m 2H), 7.31-7.20 (m, 2H), 6.19-6.15(m, 1H), 2.30-2.20 (m, 1H), 2.10-1.99 (m, 2H), 1.91-1.80 (m, 3H),1.80-1.60 (m, 3H), 1.58-1.39 (m, 7H), 1.39-1.12 (m, 9H), 1.03 (s, 3H).

Step 3 (Compound 103). To a mixture of Y2 (56 mg, 0.159 mmol) in EtOAc(5 mL) Pd/C (100 mg, 5%, wet) was added under N₂. The mixture wasstirred under H₂ (15 psi) at 15° C. for 15 hrs to give a blacksuspension, which was filtered and concentrated to give Compound 103 (10mg) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.52-8.40 (m, 2H), 7.16-7.08 (m, 2H),2.69-2.60 (m, 1H), 2.11-2.05 (m, 1H), 2.05-1.90 (m, 1H), 1.90-1.75 (m,4H), 1.71-1.52 (m, 4H), 1.52-1.45 (m, 3H), 1.38-1.22 (m, 7H), 1.22-0.95(m, 5H), 0.92-0.81 (m, 2H), 0.45 (s, 3H).

LCMS Rt=0.570 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₄H₃₆NO [M+H]⁺ 354, found 354.

Example 90. Synthesis of Compound 104

Step 1 (Z1). To a mixture of W3 (200 mg, 0.372 mmol),pyrimidin-5-ylboronic (69.1 mg, 0.558 mmol) and Na₂CO₃ (0.372 mL, 2M inwater) in THF (10 mL), was added Pd(PPh₃)₂Cl₂ (5 mg, 0.00712 mmol). Themixture was degassed under vacuum and purged with N₂. The reactionmixture was stirred at 80° C. for 5 hrs, cooled to ambient temperature,quenched with sat. aqueous NaHCO₃ (3 mL) and extracted with EtOAc (2×5mL). The combined organic layers were washed with brine (10 mL), driedover Na₂SO₄, filtered and concentrated. The residue was purified byflash chromatography on silica gel (0% to 15% of EtOAc in PE) to get Z1(140 mg, 81%) as an oil.

The structure of Compound 104 was confirmed by X-ray crystallography.

¹H NMR (400 MHz, CDCl₃) δ 9.06 (s, 1H), 8.72 (s, 2H), 6.12-6.08 (m, 1H),2.35-2.25 (s, 1H), 2.12-1.95 (m, 2H), 1.87-1.51 (m, 7H), 1.62-1.42 (m,4H), 1.42-1.38 (m, 4H), 1.38-1.12 (m, 7H), 1.00 (s, 3H), 0.91-0.81 (m,8H), 0.06 (s, 6H).

Step 2 (Z2). To a mixture of Z1 (140 mg, impure) in THF (2 mL), TBAF(199 mg, 0.598 mmol) was added. The resulting solution was stirred at80° C. for 18 hrs. Water (5 mL) was added. The mixture was extractedwith EtOAc (2×10 mL). The combined organic layers were washed with brine(5 mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash silica gel chromatography (0-30% of EtOAc in PE) togive Z2 (70 mg, 67%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 9.06 (s, 1H), 8.72 (s, 2H), 6.11-6.05 (m, 1H),2.32-2.15 (m, 1H), 2.10-1.95 (m, 2H), 1.91-1.72 (m, 4H), 1.72-1.62 (m,2H), 1.61-1.59 (m, 1H), 1.57-1.42 (m, 5H), 1.42-1.25 (m, 8H), 1.25-1.15(m, 2H), 1.00 (s, 3H).

Step 3 (Compound 104). To a mixture of Z2 (100 mg, 0.283 mmol) in EtOAc(5 mL), Pd/C (100 mg, 5%, wet) was added under N₂. The mixture wasstirred under H₂ (15 psi) at 15° C. for 15 hrs to give a blacksuspension, which was filtered and concentrated to give Compound 104 (31mg, 31%) as a solid.

¹H NMR (400 MHz, CDCl₃) 9.06 (s, 1H), 8.58 (s, 2H), 2.70-2.60 (m, 1H),2.15-1.98 (m, 2H), 1.91-1.78 (m, 4H), 1.75-1.60 (m, 2H), 1.61-1.42 (m,6H), 1.42-1.31 (m, 7H), 1.31-1.22 (m, 3H), 1.22-1.08 (m, 3H), 0.51 (s,3H).

LCMS Rt=1.017 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₃H₃₅N₂₀ [M+H]⁺ 355, found 355.

Example 91. Synthesis of Compound 105

Step 1 (AA1). To a mixture of W3 (200 mg, 0.372 mmol), (3-cyanophenyl)boronic acid (70.9 mg, 0.483 mmol) and NaOH (0.241 mL, 2M in water) inTHF (4 mL) was added Pd(dppf)Cl₂ (5 mg). The mixture was degassed undervacuum and purged with N₂. After stirring at 80° C. for 1 h, thereaction mixture was quenched with sat. aqueous NaHCO₃ (3 mL) andextracted with EtOAc (2×5 mL). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on silicagel (0% to 5% ofEtOAc in PE) to give AA1 (150 mg, 82%) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 7.63 (s, 1H), 7.60-7.57 (d, 1H), 7.52-7.47 (d,1H), 7.41-7.33 (t, 1H), 6.03-5.95 (m, 1H), 2.30-2.20 (m, 1H), 2.08-1.97(m, 1H), 1.89-1.59 (m, 7H), 1.59-1.38 (m, 6H), 1.38-1.11 (m, 9H), 1.01(s, 3H), 0.91-0.78 (m, 9H), 0.06 (s, 6H).

Step 2 (AA2). To a mixture of AA1 (150 mg) in THF (2 mL) was added TBAF(203 mg, 0.612 mmol). The reaction mixture was stirred at 80° C. for 18hrs to give a black oil. Water (5 mL) was added. The mixture wasextracted with EtOAc (2×10 mL), The combined organic layers were washedwith brine (5 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash silica gel chromatography (0˜10% of EtOAcin PE) to give AA2 (80 mg, 70%) as a solid

¹H NMR (400 MHz, CDCl₃) δ 7.63 (s, 1H), 7.60-7.57 (d, 1H), 7.52-7.47 (d,1H), 7.41-7.33 (m, 1H), 6.03-5.95 (m, 1H), 2.30-2.20 (m, 1H), 2.08-1.93(m, 2H), 1.91-1.80 (m, 3H), 1.80-1.57 (m, 4H), 1.57-1.32 (m, 5H),1.32-1.12 (m, 7H), 1.01 (s, 3H), 0.99-0.80 (m, 3H).

Step 3 (Compound 105) To a mixture of AA2 (80 mg, 0.213 mmol) in EtOAc(5 mL) was added Pd/C (100 mg, 10%, wet) under N₂. The mixture wasstirred under H₂ (15 psi) at 15° C. for 20 min to give a blacksuspension, which was filtered and concentrated to give Compound 105 (17mg, 21%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.51-7.47 (m, 2H), 7.44-7.41 (m, 1H),7.39-7.32 (m, 1H), 2.79-2.61 (m, 1H), 2.10-1.93 (m, 2H), 1.89-1.74 (m,4H), 1.71-1.60 (m, 2H), 1.59-1.45 (m, 4H), 1.45-1.37 (m, 4H), 1.37-1.19(m, 6H), 1.19-0.78 (m, 5H), 0.44 (s, 3H).

LCMS Rt=1.269 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₆H₃₄N [M+H-H₂O]⁺ 360, found 360.

Example 92. Synthesis of Compound 106

Step 1 (BB1). To a mixture of W3 (200 mg, 0.372 mmol),pyridin-3-ylboronic acid (68.5 mg, 0.588 mmol) and Na₂CO₃ (0.74 mL, 2 Min water) in 1,4-dioxane (3 mL) was added Pd(dppf)Cl₂ (5 mg, 0.00656mmol) under N₂. After stirring at 80° C. for 1 hr, the reaction mixturewas quenched with sat.

NaHCO₃ (3 mL) and extracted with EtOAc (2×5 mL) The combined organiclayers were washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography on silicagel (0% to 5% of EtOAc in PE) to give BB1 (150 mg, 87%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.69-8.60 (m, 1H), 8.49-8.40 (m, 1H),7.69-7.61 (m, 1H), 7.25-7.15 (m, 1H), 6.05-5.93 (m, 1H), 2.30-2.20 (m,1H), 2.09-1.95 (m, 2H), 1.87-1.73 (m, 4H), 1.73-1.60 (m, 2H), 1.60-1.45(m, 3H), 1.45-1.30 (m, 5H), 1.30-1.14 (m, 7H), 1.00 (s, 3H), 0.92-0.82(m, 9H), 0.06 (s, 6H).

Step 2 (BB2). To a mixture of BB1 (150 mg) in THF (2 mL), was added TBAF(214 mg, 0.644 mmol). The reaction mixture was stirred at 80° C. for 18hrs. Water (5 mL) was added to the reaction mixture. The mixture wasextracted with EtOAc (2×10 mL). The combined organic layers were washedwith brine (5 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash silica gel chromatography (0˜30% of EtOAcin PE) to give BB2 (89 mg, 79%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.69-8.60 (m, 1H), 8.49-8.40 (m, 1H),7.69-7.61 (m, 1H), 7.26-7.18 (m, 1H), 6.00-5.93 (m, 1H), 2.30-2.20 (m,1H), 2.09-1.95 (m, 2H), 1.92-1.81 (m, 3H), 1.81-1.61 (m, 3H), 1.61-1.39(m, 6H), 1.39-1.13 (m, 10H), 1.00 (s, 3H).

Step 3 (Compound 106). To a mixture of BB2 (79 mg, 0.224 mmol) in EtOAc(5 mL), Pd/C (100 mg, 5%, wet) was added under N₂. The mixture wasstirred under H₂ (15 psi) at 15° C. for 15 hrs to give a blacksuspension, which was filtered and concentrated to give Compound 106 (10mg, 21%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.50-8.40 (m, 2H), 7.55-7.49 (m, 1H),7.25-7.18 (m, 1H), 2.73-2.65 (m, 1H), 2.13-1.97 (m, 2H), 1.92-1.77 (m,4H), 1.61-1.55 (m, 4H), 1.55-1.42 (m, 4H), 1.42-1.31 (m, 5H), 1.31-1.17(m, 5H), 1.17-0.90 (m, 3H), 0.47 (s, 3H).

LCMS Rt=0.640 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₄H₃₆NO [M+H]⁺ 354, found 354.

Example 93. Synthesis of Compound 107

Step 1 (CC1). To a mixture of W3 (200 mg, 0.372 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane(101 mg, 0.502 mmol) and NaOH (0.241 mL, 2 M in water) in THF (4 mL) wasadded Pd(dppf)Cl₂ (5 mg) under N₂. The mixture was stirred at 80° C. for15 hrs and cooled to ambient temperature. The reaction mixture wasquenched with sat. aqueous NaHCO₃ (3 mL) and extracted with EtOAc (2×5mL). The combined organic layers were washed with brine (10 mL), driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography on silica gel (0% to 5% of EtOAc in PE)to give CC1 (170 mg, 97%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.87-5.80 (m, 1H), 5.68-5.64 (m, 1H),4.28-4.15 (m, 2H), 3.90-3.70 (m, 2H), 2.39-2.28 (m, 1H), 2.22-2.18 (m,3H), 1.90-1.79 (m, 5H), 1.69-1.51 (m, 4H), 1.49-1.30 (m, 5H), 1.30-1.09(m, 8H), 1.04-0.78 (m, 12H), 0.06 (s, 6H).

Step 2 (CC2). To a mixture of CC1 (170 mg) in THF (2 mL) was added TBAF(240 mg, 0.722 mmol). The reaction mixture was stirred at 80° C. for 18hrs. Water (5 mL) was added to the reaction mixture, then the mixturewas extracted with EtOAc (2×10 mL). The combined organic layers werewashed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash silica gelchromatography (0˜30% of EtOAc in PE) to give CC2 (70 mg, 55%) as asolid

¹H NMR (400 MHz, CDCl₃) δ 5.87-5.80 (m, 1H), 5.68-5.64 (m, 1H),4.28-4.15 (m, 2H), 3.90-3.76 (m, 2H), 2.39-2.28 (m, 1H), 2.28-2.07 (m,3H), 1.90-1.79 (m, 4H), 1.79-1.61 (m, 2H), 1.61-1.39 (m, 9H), 1.39-1.09(m, 8H), 0.92 (s, 3H).

Step 3 (Compound 107). To a mixture of CC2 (70 mg, 0.196 mmol) in EtOAc(5 mL), Pd/C (100 mg, 5%, wet) was added under N₂. The mixture wasstirred under H₂ (15 psi) at 15° C. for 15 hrs to give a blacksuspension, which was filtered and concentrated to give Compound 107 (37mg, 52%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 3.97-3.87 (m, 2H), 3.41-3.28 (m, 2H),1.94-1.73 (m, 6H), 1.66-1.51 (m, 5H), 1.50-1.33 (m, 8H), 1.33-1.19 (m,8H), 1.19-0.98 (m, 6H), 0.68 (s, 3H).

LCMS Rt=1.297 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₄H₃₉0 [M+H-H₂O]⁺ 343, found 343.

Example 94. Synthesis of Compound 108

Step 1 (DD1). To a mixture of W3 (200 mg, 0.372 mmol) in THF (10 mL) wasadded 2-Pyridylzinc bromide (0.966 mL, 0.5 M) and Pd(PPh₃)₄ (21.4 mg,0.0186 mmol) under N₂. The reaction mixture was stirred at 80° C. for 15hrs, then the mixture was quenched with sat. aqueous NaHCO₃ (3 mL) andextracted with EtOAc (2×5 mL). The combined organic layers were washedwith brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash silica gelchromatography (0% to 5% of EtOAc in PE) to get DD1 (170 mg, 99%) as asolid.

¹H NMR (400 MHz, CDCl₃) δ 8.58-8.52 (m, 1H), 7.60-7.52 (m, 1H),7.39-7.32 (m, 1H), 7.09-7.03 (m, 1H), 6.37-6.32 (m, 1H), 2.40-2.30 (m,1H), 2.30-2.19 (m, 1H), 2.10-1.99 (m, 1H), 1.90-1.62 (m, 6H), 1.52-1.29(m, 9H), 1.29-1.18 (m, 7H), 1.11 (s, 3H), 0.91-0.80 (m, 8H), 0.06 (s,6H).

Step 2 (DD2). To a mixture of DD1 (170 mg) in THF (2 mL) was added TBAF(242 mg, 0.728 mmol). The reaction mixture was stirred at 80° C. for 18hrs to give a black oil. Water (5 mL) was added to the oil. The mixturewas extracted with EtOAc (2×10 mL). The combined organic layers werewashed with brine (5 mL), dried over Na₂SO₄, filtered and concentrated.The residue was purified by flash silica gel chromatography (0˜10% ofEtOAc in PE) to give DD2 (90 mg, 71%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.58-8.52 (m, 1H), 7.60-7.52 (m, 1H),7.41-7.34 (m, 1H), 7.12-7.03 (m, 1H), 6.40-6.30 (m, 1H), 2.42-2.32 (m,1H), 2.28-2.19 (m, 1H), 2.09-1.99 (m, 1H), 1.92-1.79 (m, 3H), 1.79-1.62(m, 3H), 1.62-1.42 (m, 5H), 1.42-1.32 (m, 5H), 1.32-1.17 (m, 6H), 1.11(s, 3H).

Step 3 (Compound 108). To a mixture of DD2 (30 mg, 0.085 mmol) in EtOAc(5 mL) was added Pd/C (50 mg, 5%, wet) under N₂. The mixture was stirredunder H₂ (15 psi) at 15° C. for 15 hrs to give a black suspension, whichwas filtered and concentrated to give Compound 108 (11 mg, 34%) as asolid.

¹H NMR (400 MHz, CDCl₃) δ 8.58-8.52 (m, 1H), 7.61-7.51 (m, 1H),7.18-7.05 (m, 2H), 2.89-2.82 (m, 1H), 2.50-2.39 (m, 1H), 2.01-1.52 (m,8H), 1.52-1.43 (m, 3H), 1.43-1.29 (m, 6H), 1.29-1.19 (m, 5H), 1.19-0.91(m, 4H), 0.46 (s, 3H).

LCMS Rt=0.653 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₄H₃₆NO [M+H]⁺ 354, found 354.

Example 95. Synthesis of Compound 109

Step 1 (EE1). To a mixture of W3 (200 mg, 0.372 mmol) in THF (4 mL),2-(cyclopent-1-en-1-yl)-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane(93.7 mg, 0.483 mmol) and Pd(dppf)₂Cl₂ (5 mg) were added under N₂. Afterstirring at 80° C. for 15 hrs, the reaction mixture was quenched withsat. aqueous NaHCO₃ (3 mL) and extracted with EtOAc (2×5 mL). Thecombined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography on silica (0% to 5% of EtOAc in PE) to give EE1 (160 mg,95%) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 5.81-5.75 (m, 1H), 5.54-5.52 (m, 1H),2.54-2.37 (m, 4H), 2.21-2.10 (m, 1H), 1.91-1.58 (m, 7H), 1.58-1.45 (m,3H), 1.45-1.31 (m, 6H), 1.31-1.09 (m, 9H), 0.94-0.72 (m, 12H), 0.06 (s,6H).

Step 2 (EE2). To a mixture of EE1 (160 mg) in THF (2 mL), TBAF (233 mg,0.702 mmol) was added. After stirring at 80° C. for 18 hrs, theresulting black oil was treated with water (5 mL) and the mixture wasextracted with EtOAc (2×10 mL). The combined organic layers were washedwith brine (5 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash silica gel chromatography (0˜10% of EtOAcin PE) to give EE2 (90 mg, 75%) as an oil.

Step 3 (Compound 109). To a solution of EE2 (90 mg) in EtOAc (5 mL),Pd/C (100 mg, 5%, wet) was added under N₂. The mixture was stirred underH₂ (15 psi) at 15° C. for 15 hrs to give a black suspension, which wasfiltered and concentrated to give Compound 109 (33 mg, 36%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 1.91-1.80 (m, 3H), 1.80-1.73 (m, 3H),1.73-1.62 (m, 3H), 1.62-1.50 (m, 5H), 1.50-1.42 (m, 3H), 1.42-1.34 (m,5H), 1.34-1.31 (m, 1H), 1.31-1.21 (m, 5H), 1.18-1.08 (m, 4H), 1.08-0.91(m, 4H), 0.91-0.80 (m, 1H), 0.63 (s, 3H).

LCMS Rt=1.564 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₄H₃₉ [M+H-H₂O]⁺ 327, found 327.

Example 96. Synthesis of Compound 110

Step 1 (FF1). To a mixture of W3 (200 mg, 0.372 mmol), (4-cyanophenyl)boronic acid (70.9 mg, 0.483 mmol) and Pd(dppf)Cl₂ (5 mg, 0.00656 mmol)in THF (4 mL), NaOH (0.241 mL, 2 M in water) was added. The reactionmixture was stirred at 80° C. under N₂ for 1 hour, then cooled toambient temperature, treated with sat. aqueous NaHCO₃ (3 mL) andextracted with EtOAc (2×5 mL). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄, filtered, and concentrated. Theproduct was purified by flash chromatography on silica gel (0% to 5% ofEtOAc in PE) to give FF1 (230 mg, impure) as an oil.

Step 2 (FF2). To a mixture of FF1 (230 mg, impure) in THF (2 mL), TBAF(307 mg, 0.921 mmol) was added. The reaction mixture was warmed to 80°C. and stirred for 18 h to give a dark black oil, which was treated withwater (5 mL) and extracted with EtOAc (2×10 mL). The combined organiclayers were washed with brine (5 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash silica gelchromatography (0˜30% of EtOAc in PE) to give FF2 (106 mg, 76% yield for2 steps) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.62-7.53 (m, 2H), 7.49-7.41 (m, 2H),6.12-6.01 (m, 1H), 2.34-2.19 (m, 1H), 2.21-1.96 (m, 2H), 1.91-1.81 (m,3H), 1.80-1.60 (m, 3H), 1.60-1.13 (m, 16H), 1.03 (s, 3H).

Step 3 (Compound 110). To a solution of FF2 (30 mg, 0.0798 mmol) inEtOAc (5 mL) was added Pd/C (wet, 10%, 40 mg) under N₂. The suspensionwas degassed under vacuum and purged with H₂ three times. The mixturewas stirred under H₂ (15 psi) at 15° C. for 0.5 hours to give a blacksuspension. The reaction mixture was filtered and concentrated to giveCompound 110 (12 mg, 40%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.59-7.53 (m, 2H), 7.32-7.28 (m, 2H),2.81-2.67 (m, 1H), 2.12-1.95 (m, 2H), 1.89-1.78 (m, 4H), 1.71-1.60 (m,2H), 1.55-1.42 (m, 3H), 1.42-1.38 (m, 4H), 1.37-1.31 (m, 3H), 1.31-1.24(m, 6H), 1.20-1.11 (m, 1H), 1.11-1.02 (m, 1H), 1.02-0.90 (m, 1H), 0.44(s, 3H).

LCMS Rt=1.275 min in 2 min chromatography, 30-90AB, purity 99%, MS ESIcalcd. for C₂₆H₃₄N [M+H-H₂O]⁺ 360, found 360.

Example 97. Synthesis of Compound 111

Step 1 (GG1). To a mixture of W3 (200 mg, 0.372 mmol), 1-methyl-4-(4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.483mmol) and NaOH (0.241 mL, 0.482 mmol, 2M in water) in THF (4 mL) wasadded Pd(dppf)Cl₂ (5 mg). The mixture was degassed under vacuum andpurged with N₂. After stirring at 80° C. for 1 h, the reaction mixturewas quenched with sat. aqueous NaHCO₃ (3 mL) and extracted with EtOAc(2×5 mL). The combined organic layers were washed with brine (10 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography on silica gel (0% to 30% of EtOAc inPE) to give GG1 (180 mg, impure) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.35 (s, 1H), 5.75-5.71 (m, 1H),3.85 (s, 3H), 2.20-2.12 (m, 1H), 2.02-1.87 (m, 2H), 1.87-1.72 (m, 4H),1.72-1.52 (m, 4H), 1.52-1.39 (m, 6H), 1.39-1.12 (m, 12H), 0.97-0.81 (m,7H), 0.06 (s, 6H).

Step 2 (GG2). To a mixture of GG1 (180 mg, impure) in THF (2 mL) wasadded TBAF (255 mg, 0.766 mmol). The reaction mixture was stirred at 80°C. for 18 hrs to give a black oil. Water (5 mL) was added to the oil.The mixture was extracted with EtOAc (2×10 mL). The combined organiclayers were washed with brine (5 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by flash silica gelchromatography (0˜10% of EtOAc in PE) to give GG2 (100 mg, 76% for 2steps) as a solid ¹H NMR (400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.35 (s, 1H),5.81-5.70 (m, 1H), 3.87 (s, 3H), 2.32-2.12 (m, 1H), 2.02-1.91 (m, 2H),1.91-1.80 (m, 3H), 1.80-1.63 (m, 2H), 1.61-1.38 (m, 7H), 1.38-1.34 (m,1H), 1.34-1.12 (m, 9H), 0.90 (s, 3H).

Step 3 (Compound 111). To a mixture of GG2 (80 mg, 0.213 mmol) in EtOAc(5 mL) was added Pd/C (100 mg, 10%, wet) under N₂. The mixture wasstirred under H₂ (15 psi) at 15° C. for 20 min to give a blacksuspension, which was filtered and concentrated to give Compound 111 (17mg, 22%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.30 (s, 1H), 7.11 (s, 1H), 3.85 (s, 3H),2.58-2.41 (m, 1H), 2.06-1.92 (m, 1H), 1.89-1.60 (m, 6H), 1.55 (s, 3H),1.51-1.36 (m, 5H), 1.36-1.23 (m, 6H), 1.23-0.95 (m, 5H), 0.91-0.81 (m,1H), 0.47 (s, 3H).

LCMS Rt=1.075 min in 2 min chromatography, 30-90AB, purity 100%, MS ESIcalcd. for C₂₃H₃₇N₂O [M+H]⁺ 357, found 357.

Example 98. Synthesis of Compound 112

Step 1 (HH1). To a solution of U4 (2 g, 6.56 mmol) in MeOH (20 mL) wasadded NaBH₄ (495 mg, 13.1 mmol) in portions at 0° C., the reactionmixture was stirred at 0° C. for 1 h, then the mixture was stirred at15° C. for another 48 hrs. The reaction mixture was quenched with sat.aqueous NH₄Cl (20 mL) and extracted with EtOAc (3×20 mL). The combinedorganic phase was washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by flashsilica gel chromatography (0˜15% of EtOAc in PE) to give HH1 (1.5 g,75%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 3.65-3.57 (m, 1H), 2.09-2.01 (m, 1H),1.83-1.74 (m, 1H), 1.73-1.31 (m, 12H), 1.30-1.12 (m, 10H), 1.11-0.84 (m,3H), 0.77-0.74 (m, 3H), 0.73-0.69 (m, 3H).

Step 2 (Compound 112). To a solution of HH1 (200 mg, 0.652 mmol) in THF(2 mL) was added NaH (77.8 mg, 1.95 mmol, 60%) in portions at 0° C. Themixture was stirred at 25° C. for 30 min. Then, (bromomethyl)benzene(167 mg, 0.978 mmol) was added drop wise to the solution. The mixturewas stirred at 25° C. for 1 hr. The mixture was poured into water (30mL) and extracted with EtOAc (2×20 mL). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by column silica gel chromatography (petroleumether/ethyl acetate=10/1) to afford Compound 112 (30 mg, 12%) as asolid.

¹H NMR (400 MHz, CDCl₃) δ 7.36-7.30 (m, 4H), 7.24-7.21 (m, 1H), 4.54 (s,2H), 3.43-3.39 (m, 1H), 2.01-1.90 (m, 2H), 1.69-1.57 (m, 2H), 1.51-1.08(m, 18H), 0.99-0.85 (m, 3H), 0.82 (s, 3H), 0.76 (s, 3H), 0.74-0.69 (m,1H).

LCMS Rt=1.344 min in 2.0 min chromatography, 30-90 AB, purity 100%, MSESI calcd. For C₂₇H₃₉O [M−H₂O+H]⁺379, found 379.

Example 99. Synthesis of Compound 113

Step 1 (I2). A mixture of I1 (500 mg, 1.84 mmol) 10% Pd/black (50 mg)and concentrated hydrobromic acid (0.02 mL) in tetrahydrofuran (5 mL)was hydrogenated at 1 atm. for 24 h, then the mixture was filteredthrough a pad of celite and the filtrate was concentrated in vacuo.Recrystallization from acetone gave 12 (367 mg, 73%).

¹H NMR (500 MHz, CDCl₃), δ (ppm), 2.58 (t, 1H, J=14 Hz), 2.45 (dd, 1H,J=19 Hz, 9 Hz), 0.98 (s, 3H)

Step 2 (I3). To a solution of 12 (274 mg, 1.0 mmol) in methanol (4 mL)at room temperature was added iodine (0.1 mmol). After stirring at 60°C. for 12 h, the solvent was removed in vacuo. The crude product wasdissolved in dichloromethane (20 mL) and washed with saturated aqueousNaHCO₃ (15 mL), brine (20 ml), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by chromatography on basicalumina (petroleum ether/ethyl acetate=9:1) to give compound 13 (280 mg,88%).

¹H NMR (500 MHz, CDCl₃), δ (ppm), 3.19 (s, 3H), 3.13 (s, 3H), 2.43 (dd,1H, J=19.2 Hz, 8.8 Hz), 0.83 (s, 3H).

Step 3 (I4). To a suspension of methyltriphenylphosphonium bromide(10.26 g, 28.84 mmol) in THF (30 mL), was added KOt-Bu (3.23 g, 28.80mmol). The reaction was heated to 60° C. for 1 h, then 13 (3.23 g, 9.6mmol) was added to the mixture. The solution was stirred at 60° C. for15 h. The reaction mixture was diluted with EtOAc (500 mL). Theresulting mixture was washed with brine (300 mL) and evaporated invacuo. The crude residue was then purified by silica gel chromatography(PE:EtOAc=3:1) to afford 14 as a solid (2.1 g, 65%).

Step 4 (I5). To a solution of 14 (1 g, 3.1 mmol) in THF (20 mL) wasadded 2 M HCl (2 mL). The solution was stirred at rt for 1 h then thereaction mixture was extracted with EtOAc (100 mL), washed with brine(100 mL) and evaporated in vacuo. The crude residue was purified bysilica gel chromatography (PE:EtOAc=10:1) to afford 15 as a solid (710mg, 2.6 mmol 83%).

¹H NMR (500 MHz, CDCl₃), δ (ppm), 4.65 (s, 1H), 4.63 (s, 1H), 0.82 (s,3H).

Step 5 (I6). To a stirred suspension of trimethylsulfonium iodide (6.4g, 23.5 mmol) in DMSO (10 mL) was added NaH (60%; 800 mg, 31.5 mmol).After stirring at room temperature for 1 h, a suspension of compound 15(870 mg, 3.2 mmol) in DMSO (5 mL) was added dropwise. After 15 h, thereaction mixture was poured into ice-cold water and extracted with EtOAc(300 mL), washed with brine (100 mL), dried and evaporated in vacuo. Thecrude residue was then purified by silica gel chromatography(PE:EtOAc=10:1) to afford a mixture of 16 and its C-3 isomer as a solid(695 mg, 10%).

Step 6 (I7). To a solution of 16 and its C-3 isomer (129 mg, 0.45 mmol)in THF (10 mL) was added LiAlH₄ (50 mg, 1.35 mmol). The mixture wasstirred at rt for 1 h, then the reaction mixture was quenched with H₂O(5 mL) and extracted with EtOAc (100 mL). The organic layer was washedwith brine and evaporated in vacuo and the resulting crude residue waspurified by chromatography (PE:EtOAc=3:1) to afford 17 as a solid (62mg, 48%).

¹H NMR (500 MHz, CDCl₃), δ (ppm), 4.63 (s, 1H), 4.61 (s, 1H), 1.25 (s,3H), 0.82 (s, 3H).

Step 7 (I8). To a solution of 17 (86 mg, 0.3 mmol) in dry THF (5 mL) wasadded borane-tetrahydrofuran complex (1 mL; 1.0 M solution in THF).After stirring at room temperature for 1 hour, the reaction mixture wascooled in an ice bath then quenched slowly with 10% aqueous NaOH (1 mL)followed by 30% aqueous solution of H₂O₂ (1 mL). After stirring at roomtemperature for one hour, the mixture was extracted with EtOAc (3×100mL). The combined organic layers were washed with 10% aqueous Na₂S₂O₃(100 mL), brine (100 mL), dried over MgSO₄, filtered and concentrated toafford crude 18 as a solid (83 mg, 91%). The crude product was used inthe next step without further purification.

Step 8 (19). To a solution of 18 (150 mg, 0.49 mmol) in DCM (10 mL) wasadded PCC (320 mg, 1.47 mmol), and the reaction solution was stirred atrt for 2 h. The reaction mixture was then filtered through a pad ofcelite, evaporated in vacuo and the crude residue was purified by silicagel chromatography (PE:EtOAc=10:1) to afford 19 as a solid (80 mg, 53%).

¹H NMR (500 MHz, CDCl₃), δ (ppm), 9.77 (s, 1H), 2.31 (t, 1H, J=9 Hz),1.27 (s, 3H), 0.75 (s, 3H).

Step 9 (Compound 113). Trifluoroethylamine hydrochloride (90 mg, 0.66mmol) and NaNO₂ (50 mg, 0.79 mmol) were dissolved in a CH₂Cl₂/watermixture (3 mL/0.1 mL) and stirred for one hour in a sealed Schlenk tubecooled in a water/ice bath. The mixture was then further cooled to −78°C. in a dry-ice/acetone bath and stirred for 10 min, then 19 (0.1 g,0.33 mmol) and ZrCl₄ (100 mg, 0.43 mmol, 1.3 equiv) were added to themixture. After 45 min, the resulting mixture was quenched by addition ofMeOH (3 mL) followed by saturated aqueous NaHCO₃ (20 mL), extracted withCH₂Cl₂ (3×20 mL), dried over MgSO₄, and evaporated in vacuo. The cruderesidue was purified by column chromatography on silica gel(pentane/diethyl ether=10:1) to afford Compound 113 (12 mg, 9%) as asolid.

¹H NMR (500 MHz, CDCl₃), δ (ppm), 3.20 (m, 2H), 2.57 (1H, t, J=9 Hz),2.22-2.15 (m, 1H), 1.27 (s, 3H), 0.65 (s, 3H).

¹⁹FNMR (376.5 MHz, CDCl₃), δ (ppm), −62.28

Example 100. Synthesis of Compound 114 and Compound 115

Step 1 (Compound 114 and Compound 115). To a stirred solution of2,4,5-trimethyloxazole (0.37 g, 3.3 mmol) in 10 mL of THF was added LDA(2.0 M; 0.82 mL, 1.64 mmol) at −78° C. After stirring at −78° C. for 30min, a solution of 19 (0.1 g, 0.33 mmol) in 2 mL of THF was addeddropwise at −78° C. After stirring at −78° C. for 1 h, the reactionmixture was poured into ice-cold water. The mixture was extracted withEtOAc (3×100 mL), washed with brine (3×100 mL), dried (MgSO₄), filtered,and evaporated in vacuo. The resulting crude residue was purified byprep-HPLC to afford Compound 114 (54 mg, 35% yield) as a solid, andCompound 115 (22 mg, 16.1% yield) as a solid.

Compound 114

¹H NMR (500 MHz, CDCl₃), δ (ppm), 4.0 (1H, t, J=7 Hz), 3.68 (s, 1H),2.94 (1H, d, J=13 Hz), 2.70 (dd, 1H, J=16 Hz, 10 Hz), 2.20 (s, 3H), 2.03(s, 3H), 1.26 (s, 3H), 0.72 (s, 3H).

Compound 115

¹H NMR (500 MHz, CDCl₃), δ (ppm), 3.96 (1H, t, J=7 Hz), 3.40-3.60 (1H,br), 2.82 (1H, d, J=13 Hz), 2.62 (dd, 1H, J=16 Hz, 9 Hz), 2.20 (s, 3H),2.03 (s, 3H), 1.26 (s, 3H), 0.78 (s, 3H).

Example 101. Synthesis of Compound 116 and Compound 117

Step 1 (Compound 116 and Compound 117). To a stirred solution of2,4,5-trimethylthiazole (0.21 g, 1.64 mmol) in 10 mL of THF was addednBuLi (2.5 M; 0.66 mL, 1.64 mmol) at −78° C. After stirring at −78° C.for 30 min, a solution of 19 (0.1 g, 0.33 mmol) in 2 mL of THF was addeddropwise at −78° C. After stirring at −78° C. for 1 h, the reactionmixture was poured into ice-cold water and extracted with EtOAc (3×100mL), washed with brine (3×100 mL), dried (MgSO₄), filtered, andevaporated in vacuo, then purified by prep-HPLC to afford Compound 116(44 mg, 31% yield) as a solid and Compound 117 (27 mg, 19% yield) as asolid.

Compound 116

¹H NMR (500 MHz, CDCl₃), δ (ppm), 4.10 (bs, 1H), 3.97 (t, 1H, J=8.6 Hz),3.14 (dd, 1H, J=15.3 Hz, J=2.8 Hz), 2.88 (dd, 1H, J=14.8 Hz, J=9.6 Hz),2.30 (s, 3H), 2.27 (s, 3H), 1.25 (s, 3H), 0.72 (s, 3H).

Compound 117

¹H NMR (500 MHz, CDCl₃), δ (ppm), 3.91 (t, 1H, J=8.4 Hz), 3.03 (dd, 1H,J=14.4 Hz, J=1.9 Hz), 2.78 (dd, 1H, J=14.4 Hz, J=7.8 Hz), 2.30 (s, 3H),2.27 (s, 3H), 1.25 (s, 3H), 0.77 (s, 3H).

Example 102. Synthesis of Compound 118

The synthesis of 1A is described in WO 2015/010054.

Step 1: Hydroxylamine hydrochloride (154 mg, 2.2 mmol) was added to asolution of compound 1A (350 mg, 1.09 mmol) in anhydrous pyridine (10mL). The solution was allowed to stir at 20° C. for 12 h. The reactionmixture was poured into water (20 mL). The solid was collected and driedto give compound 1B (280 mg, 76%) as an off-solid.

¹H NMR: (400 MHz, CDCl₃) δ 6.82 (br, 1H), 3.92-3.85 (m, 1H), 3.31-3.22(m, 4H), 2.47-2.37 (m, 2H), 1.90-1.52 (m, 6H), 1.45-0.94 (m, 12H), 0.87(s, 3H), 0.82 (s, 3H), 0.78-0.67 (m, 1H).

Step 2: A solution of KHCO₃ (500 mg, 5 mmol) in H₂O (5 mL) was added toa solution of NBS (440 mg, 2.5 mmol) in dioxane (5 mL). The suspensionwas allowed to stir at room temperature for 0.25 h and a solution ofcompound 1B (280 mg, 0.835 mmol) in dioxane (10 mL) was added indropwise manner. A pale green color rapidly developed, and the reactionwas allowed to stir at room temperature for 10 h. The solution wascooled to 0° C. and NaBH₄ (220 mg, 5.85 mmol) was added in portions. Alarge amount of gas evolution was observed and the reaction was allowedto stir overnight, gradually warming to room temperature. The reactionwas quenched with saturated aqueous NH₄Cl (20 mL). The resultingsuspension was partitioned between water (20 mL) and EtOAc (50 mL), andthe organic layer was separated. The aqueous layer was then extractedwith EtOAc (3×20 mL) and organic extracts combined, washed with brine(20 mL), dried (Na₂SO₄), and concentrated under reduced pressure. Theresulting oil was purified by column chromatography on silica gel(petrol ether: ethyl acetate=5:1) to give Compound 118 (70 mg, 24%) asan off-white powder.

¹H NMR: (400 MHz, CDCl₃) δ 4.36 (t, J=8.8 Hz, 1H), 3.99-3.92 (m, 1H),3.37-3.30 (m, 4H), 2.60-2.48 (m, 1H), 2.12-2.02 (m, 2H), 1.95-1.62 (m,5H), 1.50-1.38 (m, 3H), 1.37-1.23 (m, 8H), 1.03-0.94 (m, 1H), 0.93 (s,3H), 0.80-0.75 (m, 1H), 0.71 (s, 3H).

Example 103. Synthesis of Compound 119

The synthesis of 2A is described in WO 2015/010054.

Step 1: Hydroxylamine hydrochloride (178 mg, 2.58 mmol) was added to 2A(300 mg, 0.86 mmol) in anhydrous pyridine (3 mL). The solution wasallowed to room temperature for 12 hours. Water was added slowly, thenthe off-solid was precipitated. The solid was filtered and evaporated todryness. 2B (200 mg, 64%) was collected. It was used to next stepwithout purification.

¹H NMR: (400 MHz, methanol-d₄) δ 3.83-3.80 (m, 1H), 3.81-3.70 (m, 1H),2.44-2.43 (m, 3H), 1.95-1.11 (m, 12H), 1.09 (s, 3H), 1.03 (s, 3H),1.02-0.98 (m, 1H), 0.88-0.81 (m, 1H).

Step 2: A solution of K₂CO₃ (330 mg, 3.3 mmol) in H₂O (3 mL) was addedto a solution of NBS (290 mg, 1.65 mmol) in dioxane (2 mL). Thesuspension was allowed to stir at room temperature for 15 minutes and 2B(200 mg, 0.55 mmol) in dioxane (3 mL) was added in a dropwise manner. Apale green color rapidly developed, and the reaction was allowed to stirat room temperature for 10 hours. The solution was cooled to 0° C. andNaBH₄ (146.3 mg, 3.85 mmol) was added in portions. A large amount of gasevolution was observed and the reaction was allowed to stir overnight,gradually warming to room temperature. The reaction was quenched withsaturated aqueous NH₄Cl (30 mL) and extracted with EtOAc (3×50 mL). Theorganic extracts combined, washed with brine (100 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography (petroleum ether: ethylacetate=10:1) to afford Compound 119 (73 mg, 35%) as an off-solid.

¹H NMR: (400 MHz, CDCl₃) δ 4.33-4.30 (m, 1H), 3.96-3.95 (m, 1H),3.71-3.31 (m, 1H), 3.34-3.30 (m, 4H), 3.23 (s, 3H), 2.55-2.51 (m, 2H),2.10-1.92 (m, 1H), 1.89-1.74 (m, 5H), 1.54-1.10 (m, 9H), 1.08 (s, 3H),0.98-0.91 (m, 1H), 0.89 (s, 3H), 0.79-0.76 (m, 1H).

Example 104. Syntheses of Compounds 120 and 121

The synthesis of 3A is described in WO 2015/010054.

Step 1: Hydroxylamine hydrochloride (509 mg, 7.32 mmol) was added to 3A(800 mg, 2.38 mmol) in anhydrous pyridine (5 mL). The solution wasallowed to stir at room temperature for 12 hours. The mixture wasextracted with EtOAc (50 mL) and H₂O (40 mL). The organic phase waswashed with HCl (80 mL, 0.5 M), dried over Na₂SO₄ and evaporated to givethe crude product 3B (700 mg, 84%) as an off-solid.

Step 2: A solution of K₂CO₃ (1.20 g, 11.96 mmol) in H₂O (8 mL) was addedto a solution of NBS (1.05 g, 5.97 mmol) in dioxane (3 mL). Thesuspension was allowed to stir at room temperature for 15 minutes and 3B(700 mg, 1.99 mmol) in dioxane (3 mL) was added in a dropwise manner.The reaction was allowed to stir at room temperature for 10 hours. Thesolution was cooled to 0° C. and NaBH₄ (529.34 mg, 13.93 mmol) was addedin portions. A large amount of gas evolution was observed and thereaction was allowed to stir overnight, gradually warming to roomtemperature. The reaction was quenched with saturated aqueous NH₄Cl (30mL) and extracted with EtOAc (3×50 mL). The organic extracts combined,washed with brine (100 mL), dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (petroleum ether: ethyl acetate=10:1) toafford Compound 120 (400 mg, 55%) as an off-solid.

¹H NMR: (400 MHz, CDCl₃) δ 4.41-4.33 (m, 1H), 4.30-4.28 (m, 1H),3.97-3.90 (m, 1H), 3.36-3.35 (m, 4H), 2.56-2.52 (m, 1H), 2.25-2.21 (m,1H), 2.08-2.00 (m, 2H), 1.89-1.53 (m, 4H), 1.51-1.20 (m, 8H), 1.17-1.10(m, 4H), 1.09-1.07 (m, 1H), 1.10-0.94 (m, 4H), 0.83-0.79 (m, 1H).

Step 3: To a stirred solution of Compound 120 (250 mg, 0.68 mmol) inCH₂Cl₂ (3 mL) was added Ac₂O (69.54 mg, 0.68 mmol) and DMAP (17 mg, 0.14mmol). Then Et₃N (137.5 mg, 1.36 mmol) was added. The mixture wasstirred at room temperature for 3 hours. The mixture was treated withwater and extracted with CH₂Cl₂ (2×50 mL), and the organic layer waswashed with brine (100 mL), dried over anhydrous Na₂SO₄, thenconcentrated to obtain crude product 3C (200 mg, 80%), which was used tothe next step without purification.

Step 4: To a stirred solution of 3C (200 mg, 0.49 mmol) in CH₂Cl₂ (3 mL)was added PCC (211 mg, 0.98 mmol). The mixture was stirred at roomtemperature for 12 hours. The mixture was filtered, and the filtrate wasconcentrated to give the crude product, which was purified by flashcolumn chromatography on silica gel (petroleum ether: ethyl acetate=5:1)to afford 3D (130 mg, 65%) as an off-solid.

Step 5: To a stirred solution of 3D (130 mg, 0.32 mmol) in MeOH (3 mL)and H₂O (1 mL) was added LiOH (60.8 mg, 1.60 mmol). The mixture wasstirred at 50° C. for 4 hours. The solvent was removed, and the residuewas treated with water, then extracted with EtOAc (2×50 mL). The organicphase was washed with brine (100 mL), dried over anhydrous Na₂SO₄, thenevaporated to give the crude product, which was purified by preparativeHPLC to afford Compound 121 (41 mg, 18%) as an off-solid.

¹H NMR: (400 MHz, CDCl₃) δ 4.57-4.52 (m, 1H), 4.30-4.28 (m, 1H),3.93-3.92 (m, 1H), 3.37 (s, 3H), 3.28-3.27 (m, 1H), 2.78-2.74 (m, 1H),2.64-2.57 (m, 2H), 2.46-2.43 (m, 1H), 2.25-2.19 (m, 1H), 1.90-1.73 (m,6H), 1.53-1.48 (m, 2H), 1.33-1.20 (m, 3H), 1.18-1.10 (m, 5H), 0.68 (s,3H).

Example 105. Syntheses of Compounds 5 and 6

The synthesis of 4A is described in WO 2015/010054.

Step 1: A solution of 4A (2.0 g, 6.57 mmol) in EtOH (20 mL) was treatedwith 5 drops of fuming H₂SO₄ at room temperature. After 1 hour, thereaction mixture was quenched with aqueous NaHCO₃ (10 mL). The resultingsolution was extracted with 2×100 mL of ethyl acetate and the organiclayers combined and dried over anhydrous sodium sulfate. The organicphase was concentrated under vacuum. The crude product was purified bycolumn chromatography on silica gel (petroleum ether: ethyl acetate=6:1)to give 4B (800 mg, 35%) as an off-solid.

¹H NMR: (400 MHz, CDCl₃) δ 4.44-4.41 (m, 1H), 3.94-3.93 (m, 1H),3.61-3.57 (m, 1H), 3.45-3.454 (m, 1H), 3.42-3.41 (m, 1H), 2.50-2.44 (m,1H), 2.09-1.83 (m, 7H), 1.61-1.58 (m, 3H), 1.45-1.20 (m, 14H), 1.18-1.12(m, 4H), 1.10 (s, 3H), 1.06-1.02 (m, 1H), 0.83-0.80 (m, 1H).

Step 2: Hydroxylamine hydrochloride (458 mg, 6.60 mmol) was added to 4B(770 mg, 2.20 mmol) in anhydrous pyridine (5 mL). The solution wasallowed to stir at room temperature for 12 hours. The mixture wasextracted with EtOAc (100 mL) and H₂O (80 mL). The organic phase waswashed with HCl (80 mL, 0.5 M), dried over Na₂SO₄ and evaporated to givethe crude product 4C (720 mg, 90%) as an off-solid.

Step 3: A solution of K₂CO₃ (1.15 g, 11.5 mmol) in H₂O (5 mL) was addedto a solution of NBS (1.0 g, 5.73 mmol) in dioxane (3 mL). Thesuspension was allowed to stir at room temperature for 15 minutes and 4C(700 mg, 1.91 mmol) in dioxane (3 mL) was added in a dropwise manner.The reaction was allowed to stir at room temperature for 10 hours. Thesolution was cooled to 0° C. and NaBH₄ (508.46 mg, 13.37 mmol) was addedin portions. A large amount of gas evolution was observed and thereaction was allowed to stir overnight, gradually warming to roomtemperature. The reaction was quenched with saturated aqueous NH₄Cl (30mL) and extracted with EtOAc (3×50 mL). The organic extracts combined,washed with brine (100 mL), dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (petroleum ether: ethyl acetate=5:1) toafford the Compound 5 (350 mg, 48%) as an off-solid.

¹H NMR: (400 MHz, CDCl₃) δ 4.41-4.40 (m, 1H), 4.33-4.28 (m, 1H),4.00-3.90 (m, 1H), 3.62-3.60 (m, 1H), 3.45-3.42 (m, 1H), 3.40-3.38 (m,1H), 2.56-2.53 (m, 1H), 2.25-2.21 (m, 1H), 2.10-2.00 (m, 2H), 1.89-1.70(m, 4H), 1.54-1.19 (m, 8H), 1.18-1.15 (m, 7H), 1.12-1.10 (m, 1H),1.05-0.98 (m, 4H), 0.83-0.79 (m, 1H).

Step 4: To a stirred solution of Compound 122 (350 mg, 0.92 mmol) inCH₂Cl₂ (3 mL) was added Ac₂O (93.6 mg, 0.92 mmol) and DMAP (22.5 mg,0.18 mmol). Then Et₃N (196.2 mg, 1.94 mmol) was added. The mixture wasstirred at room temperature for 3 hours. The mixture was treated withwater and extracted with CH₂Cl₂ (2×50 mL), and the organic layer waswashed with brine (100 mL), dried over anhydrous Na₂SO₄, thenconcentrated to obtain crude 4D (147 mg, 38%), which was used in thenext step without purification.

Step 5: To a stirred solution of 4D (110 mg, 0.26 mmol) in CH₂Cl₂ (3 mL)was added PCC (112 mg, 0.52 mmol). The mixture was stirred at roomtemperature for 12 hours. The mixture was filtered, and the filtrate wasconcentrated to give the crude product, which was purified by flashcolumn chromatography (petroleum ether: ethyl acetate=5:1) to afford 4E(88 mg, 81%) as an off-solid.

¹H NMR: (400 MHz, CDCl₃) δ 4.92-4.90 (m, 1H), 4.56-4.52 (m, 1H),3.67-3.63 (m, 1H), 3.45-3.40 (m, 2H), 2.78-2.75 (m, 1H), 2.64-2.61 (m,2H), 2.46-2.42 (m, 1H), 2.26-2.19 (m, 1H), 2.05 (s, 3H), 1.91-1.70 (m,5H), 1.51-1.20 (m, 6H), 1.18-1.15 (m, 6H), 1.104-1.00 (m, 1H), 0.90-0.80(m, 2H), 0.68 (s, 3H).

Step 6: To a stirred solution of 4E (88 mg, 0.21 mmol) in MeOH (2 mL)and H₂O (1 mL) was added LiOH (40 mg, 1.68 mmol). The mixture wasstirred at 50° C. for 4 hours. The solvent was removed, and the residuewas treated with water, then extracted with EtOAc (2×30 mL). The organicphase was washed with brine (50 mL), dried over anhydrous Na₂SO₄. thenevaporated to give the crude product, which was purified by flash columnchromatography on silica gel (petroleum ether: ethyl acetate=3:1) toafford the Compound 123 (28 mg, 34%) as an off-solid.

¹H NMR: (400 MHz, CDCl₃) δ 4.57-4.52 (m, 1H), 3.91-3.90 (m, 1H),3.75-3.70 (m, 1H), 3.39-3.34 (m, 2H), 2.74-2.69 (m, 1H), 2.66-2.61 (m,2H), 2.45-2.42 (m, 1H), 1.90-1.77 (m, 5H), 1.41-1.36 (m, 1H), 1.33-1.20(m, 6H), 1.18-1.15 (m, 8H), 1.33-1.20 (m, 3H), 0.90-0.81 (m, 1H), 0.68(s, 3H).

Example 106. Syntheses of Compounds 124 and 125

The synthesis of 5A is described in WO 2015/010054.

Step 1: To a solution of mixture 5A (0.6 g, 2 mmol) in pyridine (5 mL)was added benzoyl chloride (0.8 g, 5.7 mmol). The mixture was thenstirred at 20° C. for 2 hours. To the mixture was then added aq. NaHCO₃,extracted with ethyl acetate. The organic layer was separated, driedover Na₂SO₄, concentrated under vacuum to give mixture 5B (0.9 g, crude)as a light yellow oil.

¹H NMR: (400 MHz, CDCl₃) δ 8.10-8.00 (m, 2H), 7.58-7.52 (m, 1H),7.49-7.40 (m, 2H), 5.09-5.00 (m, 1H), 2.49-2.39 (m, 1H), 2.20-1.45 (m,14H), 1.40-0.75 (m, 15H).

To a solution of mixture 5B (0.9 g, crude) in THF (4 mL) and MeOH (6 mL)was added CeCl₃.7H₂O (0.87 g, 2.2 mmol). The mixture was stirred at 0°C. for 15 minutes. NaBH₄ (90 mg, 2.4 mmol) was then added in portions at0° C. as monitored by TLC. To the mixture was then added aq. NH₄Cl andthen extracted with ethyl acetate. The organic layer was separated,dried over Na₂SO₄, concentrated under vacuum, purified by columnchromatography on silica gel (petrol ether: ethyl acetate=8:1 to 5:1) togive mixture 5C (0.6 g, 73% of 2 steps) as an off-solid.

¹H NMR: (400 MHz, CDCl₃) δ 8.08-8.00 (m, 2H), 7.58-7.52 (m, 1H),7.49-7.41 (m, 2H), 5.08-4.98 (m, 1H), 3.64 (t, J=8.6 Hz, 1H), 2.20-0.65(m, 31H).

Step 2: To a suspension of NaH (120 mg, 60%, 3 mmol) in THF (3 mL) wasadded a solution of mixture 5D (0.6 g, 1.5 mmol) in THF (2 mL). Themixture was stirred at 0° C. for 30 minutes. MeI (850 mg, 6 mmol) wasthen added and the mixture was then stirred at 40° C. for 5 hours. Themixture was then poured into aq. NH₄Cl, extracted with ethyl acetate.The organic layer was separated, dried over Na₂SO₄, concentrated undervacuum, purified by column chromatography on silica gel (petrol ether:ethyl acetate=40:1). The mixture was then subjected to SFC to obtain 5D(350 mg) and 5E (100 mg, total yield: 72%) as off-solids.

¹H NMR (5D): (400 MHz, CDCl₃) δ 8.20-8.08 (m, 2H), 7.63-7.55 (m, 1H),7.52-7.44 (m, 2H), 5.08-5.00 (m, 1H), 3.37 (s, 3H), 3.24 (t, J=8.4 Hz,1H), 2.20-1.40 (m, 13H), 1.37-0.70 (m, 17H).

¹H NMR (5E): (400 MHz, CDCl₃) δ 8.20-8.08 (m, 2H), 7.61-7.53 (m, 1H),7.51-7.42 (m, 2H), 5.10-5.04 (m, 1H), 3.36 (s, 3H), 3.24 (t, J=8.4 Hz,1H), 2.08-1.15 (m, 16H), 1.07-0.70 (m, 14H).

Step 3a: To a solution of 5D (150 mg, 0.35 mmol) in THF (4 mL) was addedMeOH (2 mL) and a solution of LiOH.H₂O (0.3 g, 7 mmol) in water (1 mL).The mixture was stirred at 30° C. for 2 days. The mixture was extractedwith ethyl acetate. The organic layer was dried over Na₂SO₄, purified bycolumn chromatography (petrol ether: ethyl acetate=10:1) to giveCompound 124 (61 mg, 55%) as an off-solid.

¹H NMR: (400 MHz, CDCl₃) δ 3.80-3.75 (m, 1H), 3.34 (s, 3H), 3.21 (t,J=8.4 Hz, 1H), 2.05-1.09 (m, 19H), 0.95-0.83 (m, 8H), 0.77-0.67 (m, 4H).

Step 3b: To a solution of 5E (300 mg, 0.7 mmol) in THF (4 mL) was addedMeOH (2 mL) and a solution of LiOH.H₂O (0.3 g, 7 mmol) in water (1 mL).The mixture was stirred at 30° C. for 2 days. The mixture was extractedwith ethyl acetate. The organic layer was dried over Na₂SO₄, purified bycolumn chromatography on silica gel (petrol ether: ethyl acetate=10:1)to give Compound 125 (189 mg, 86%) as a solid.

¹H NMR (ST-400-135): (400 MHz, CDCl₃) δ 3.75-3.65 (m, 1H), 3.34 (s, 3H),3.21 (t, J=8.4 Hz, 1H), 2.05-1.84 (m, 3H), 1.75-1.08 (m, 16H), 1.05-0.82(m, 8H), 0.76-0.64 (m, 4H).

Example 107. Synthesis of Compound 126

The synthesis of 6A is described in WO 2015/010054.

Step 1: To a solution of 6A (0.3 g, 0.9 mmol) in DMF (5 mL) was addedimidazole (0.18 g, 2.7 mmol) and TBSCl (0.27 g, 1.8 mmol). The mixturewas stirred at 25° C. for 16 hours. To the mixture was added water,extracted with petrol ether/ethyl acetate (8:1). The organic layer wasseparated, dried over Na₂SO₄, concentrated under vacuum to give 6B (0.4g, quantitative) as an oil.

¹H NMR: (400 MHz, CDCl₃) δ 3.78-3.68 (m, 2H), 3.23 (s, 3H), 2.52-2.43(m, 1H), 2.30-2.20 (m, 1H), 2.06-1.88 (m, 4H), 1.70-0.70 (m, 32H), 0.13(s, 6H).

Step 2: To a solution of 6B (0.4 g, 0.9 mmol) in tetrahydrofuran (2 mL)and MeOH (4 mL) was added NaBH₄ (0.08 g, 2 mmol) at 0° C. The mixturewas stirred at 0° C. for 5 minutes. NH₄Cl (aq.) was then added. Themixture was extracted with ethyl acetate. The combined organic layer wasseparated, dried over Na₂SO₄, concentrated under vacuum to give 6C (0.5g, crude product) as an off-solid.

¹H NMR: (400 MHz, CDCl₃) δ 3.75-3.55 (m, 2H), 3.22 (s, 3H), 2.30-2.25(m, 1H), 2.08-2.00 (m, 1H), 1.70-1.55 (m, 6H), 1.50-1.08 (m, 9H),0.98-0.85 (m, 22H), 0.11 (s, 6H).

Step 3: To a solution of 6C (0.5 g, 1.1 mmol) in tetrahydrofuran (5 mL)was added NaH (0.2 g, 60%, 5 mmol) at 15° C. The mixture was stirred at25° C. for 30 minutes. To the mixture was then added MeI (1.4 g, 10mmol). The mixture was stirred at 25° C. for 16 hours. To the mixturewas then added NH₄Cl (aq.), extracted with ethyl acetate. The organiclayer was then separated, dried over anhydrous sodium sulfate,concentrated under vacuum to give 6D (0.5 g, crude) as an off-solid.

¹H NMR: (400 MHz, CDCl₃) δ 3.75-3.62 (m, 2H), 3.35 (s, 3H), 3.25-3.15(m, 4H), 2.40-2.30 (m, 1H), 2.03-1.92 (m, 1H), 1.70-1.60 (m, 3H),1.50-0.75 (m, 32H), 0.14 (s, 6H).

Step 4: To a solution of 6D (0.5 g, 1.1 mmol) in CH₂Cl₂ (5 mL) was addedCF₃COOH (0.5 mL). The mixture was stirred at 25° C. for 3 hours. To themixture was then added NaHCO₃ (aq.). The organic layer was separated,dried over anhydrous sodium sulfate, concentrated under vacuum, purifiedby column chromatography (petrol ether:ethyl acetate=8:1) to givecompound 125 (119 mg, 37% over 3 steps) as an off-solid.

¹H NMR: (400 MHz, CDCl₃) δ 3.83-3.75 (m, 1H), 3.70-3.63 (m, 1H), 3.36(s, 3H), 3.25 (s, 3H), 3.20 (t, J=8 Hz, 1H), 2.42-2.30 (m, 1H),2.05-1.95 (m, 1H), 1.85-1.72 (m, 3H), 1.65-1.10 (m, 12H), 1.05-0.90 (m,11H), 0.83-0.75 (m, 1H).

Example 108. Synthesis of Compound 127

Step 1: To a solution of 7A (50 g, 146 mmol) and Pd/C (2.5 g, 10%Palladium on carbon, 50% water wet) in THF (500 mL) was addedconcentrated hydrobromic acid (1.0 mL, 48% in water). The reaction washydrogenated under 15 psi of hydrogen at 25° C. for 16 h. The reactionwas conducted in parallel for 4 times. The reaction mixture was filteredthrough a pad of celite and washed with THF (1 L×3) and DCM (1 L×3). Thefiltrate was concentrated in vacuum to give 7B (196 g, crude).

¹H NMR (400 MHz, CDCl₃) δ 2.64-2.53 (m, 1H), 2.52-2.41 (m, 1H),2.30-2.03 (m, 6H), 2.01-1.91 (m, 1H), 1.90-1.69 (m, 3H), 1.68-1.48 (m,5H), 1.47-1.29 (m, 4H), 1.28-1.13 (m, 2H), 0.68 (s, 3H).

Step 2: To a solution of 2,6-di-tert-butyl-4-methylphenol (240 g, 1.08mol) in toluene (150 mL) was added drop-wise AlMe₃ (270 mL, 540 mmol, 2M in toluene) at 0° C. The mixture was stirred at 25° C. for 1 h. 7B (50g, 182 mmol) in toluene (200 mL) was added drop wise to the solution at−70° C. After stirring at −70° C. for 1 h, MeMgBr (63.6 ml, 190 mmol, 3Min ethyl ether) was added drop wise at −70° C. The resulting solutionwas stirred at −70° C. for 1 hrs. The reaction was quenched by saturatedaqueous NH₄Cl (200 mL) at −70° C. After stirring at 25° C. for 0.5 h,the resulting mixture was filtered through a celite pad and the pad waswashed with EtOAc (500 mL). The combined organic layer was separated,washed with brine (500 mL×2) and concentrated in vacuum. The crudeproduct was purified by silica gel column eluted with PE/EtOAc=50/1 to3/1 to give 7C (25 g, 47%) as an off-solid.

¹H NMR (400 MHz, CDCl₃) δ 2.47-2.40 (m, 1H), 2.12-2.03 (m, 1H),1.96-1.75 (m, 6H), 1.71-1.61 (m, 1H), 1.54-1.32 (m, 7H), 1.30-1.02 (m,11H), 0.86 (s, 3H).

Step 3: To a solution of 7C (0.1 g, 0.34 mmol) in THF (5 mL) was addedMeLi (4.29 mL, 1.6 M) at 15° C. The mixture was stirred at 15° C. for 16h and 50° C. for 1 h and quenched with NH₄Cl (5 mL, sat.). The mixturewas extracted with EtOAc (20 mL). The organic layer was separated, driedover Na₂SO₄, filtered and concentrated in vacuum to give a crudematerial, which was purified by silica gel column (PE/EtOAc=4/1 to 3/1)to give crude Compound 126 (80 mg) as an off-solid. The crude productwas dissolved in MeCN (10 mL) at 50° C. Water (3 mL) was added. Themixture was concentrated in vacuum at 15° C. to 5 mL and an off-solidwas formed. The mixture was filtered. The solid was washed withMeCN/water (5 mL, 1:1), dried in vacuum to give Compound 126 (49 mg,yield: 47%) as an off-solid.

¹H NMR (400 MHz, CDCl₃) δ 1.90-1.60 (m, 7H), 1.57-1.38 (m, 8H),1.37-1.18 (m, 13H), 1.17-0.99 (m, 3H), 0.85 (s, 3H).

LCMS Rt=0.818 min in 2.0 min chromatography, 30-90 AB, purity 100%, MSESI calcd. for C₂₀H₃₁ [M+H-2H₂0]⁺ 271, found 271.

TABLE 2 TBPS Data Compound TBPS IC₅₀ Compound structure number (nM)

 1 C

 2 D

 3 A

 4 B

 5 C

 6 E

 7 E

 8 C

 9 D

 10 D

 11 E

 12 E

 13 D

 14 E

 15 D

 16 D

 17 D

 18 C

 19 D

 20 D

 21 B

 22 E

 23 D

 24 E

 25 D

 26 D

 27 D

 28 D

 29 E

 30 D

 31 C

 32 B

 33 D

 34 D

 35 D

 36 —

 37 B

 38 A

 39 C

 40 A

 41 A

 42 B

 43 B

 44 C

 48 D

 49 C

 50 D

 55 E

 56 D

 57 D

 58 E

 60 E

 61 D

 63 D

 64 C

 65 D

 66 C

 69 D

 70 D

 73 C

 74 E

 75 B

 76 A

 77 B

 78 C

 79 D

 80 E

 83 D

 84 B

 85 E

 86 D

 87 D

 88 E

 89 D

 90 D

 91 E

 92 E

 93 E

 94 E

 95 E

 96 E

 97 E

 98 E

 99 E

100 E

101 D

102 D

103 B

104 C

105 B

106 B

107 E

108 D

109 E

110 B

111 C

112 E

118 B

119 B

120 D

121 D

122 D

123 C

125 B

125 D

126 E For Table 2: TBPS: A” indicates an IC₅₀ <10 nM, “B” indicates anIC₅₀ 10 to <50 nM, “C” indicates an IC₅₀ 50 nM to <100 nM, “D” indicatesan IC₅₀ 100 nM to <500 nM, and “E” indicates IC₅₀ greater than or equalto 500 nM.

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1. A compound of Formula (1-A):

or a pharmaceutically acceptable salt thereof, wherein: R³ is alkyl,alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each of R^(X)and R^(Y) is independently hydrogen, aryl, or alkyl R¹⁹ is hydrogen oralkyl; R⁵ is absent or hydrogen; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent; 2-68. (canceled)
 69. The compound ofclaim 1, wherein R³ is alkyl.
 70. The compound of claim 69, wherein thealkyl is a substituted alkyl.
 71. The compound of claim 1, wherein R^(X)and R^(Y) are not both hydrogen.
 72. The compound of claim 1, whereinone of R^(X) and R^(Y) is hydrogen and the other aryl.
 73. The compoundof claim 1, wherein one of R^(X) and R^(Y) is alkyl and the other aryl.74. The compound of claim 1, wherein R¹⁹ is hydrogen.
 75. The compoundof claim 1, wherein R¹⁹ is alkyl.
 76. The compound of claim 75, whereinthe alkyl is a substituted alkyl.
 77. The compound of claim 1, wherein

is a single bond and R⁵ is hydrogen.
 78. A compound of Formula (II-c):

or a pharmaceutically acceptable salt thereof, wherein: each of R², R⁴,R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen, halogen, cyano,nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR_(A1), —S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1); R³ isalkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R⁵ isabsent or hydrogen; R¹⁹ is hydrogen or alkyl; each of R^(21a) andR^(21b) is independently hydrogen, halogen, cyano, nitro, alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —OR^(A1),—SR^(A1), —N(R^(A1))₂, —NHC(═O)R^(A1), —NHC(═O)OR^(A1), —S(═O)R^(A2),—SO₂R^(A2), or —S(═O)₂OR^(A1); or R^(21a) and R^(21b) together with thecarbon atom to which they are attached form a carbocyclyl, heterocyclyl,or —C(═O)— group; Q is —N(R^(A1))(R^(A1)); each instance of R^(A1) isindependently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attachedto an oxygen atom, a sulfur protecting group when attached to a sulfuratom, a nitrogen protecting group when attached to a nitrogen atom, ortwo R^(A1) groups are joined to form an heterocyclic or heteroaryl ring;R^(A2) is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl; n is an integer selected from 1, 2, and 3; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent.
 79. The compound of claim 78, whereinthe compound of Formula (II-c) is a compound of the Formula (II-d):


80. The compound of claim 79, wherein R¹⁹ is hydrogen.
 81. The compoundof claim 78, wherein the compound of Formula (II-c) is a compound of theFormula (III-a):

or a pharmaceutically acceptable salt thereof, wherein: each of R², R⁴,R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen; Q is—N(R^(A1))(R^(A1)); each instance of R^(A1) is independently hydrogen,alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R¹⁹ isunsubstituted alkyl; and

represents a single bond and R⁵ is hydrogen.
 82. The compound of claim78, wherein the compound of Formula (II-c) is a compound of the Formula(III-b):

or a pharmaceutically acceptable salt thereof, wherein: each of R², R⁴,R⁶, R⁷, R^(11a), and R^(11b) is independently hydrogen; Q is—N(R^(A1))(R^(A1)); each instance of R^(A1) is independently hydrogen,alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R¹⁹ is—C(R^(C))₂OR^(A1), wherein R^(C) is hydrogen or alkyl; and

represents a single bond and R⁵ is hydrogen.
 83. A compound, orpharmaceutically acceptable salt thereof, selected from the groupconsisting of:


84. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable excipient.
 85. A method for treating aCNS-related disorder in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound ofclaim
 1. 86. The method of claim 85, wherein the CNS-related disorder isa sleep disorder, a mood disorder, an anxiety disorder, a schizophreniaspectrum disorder, a convulsive disorder, a disorder of memory and/orcognition, a movement disorder, a personality disorder, autism spectrumdisorder, pain, traumatic brain injury, a vascular disease, a substanceabuse disorder and/or withdrawal syndrome, or tinnitus.
 87. A kitcomprising a solid composition comprising a compound of claim 1 and asterile diluent.